A Case for the Neuroprotective Potential of African Phytochemicals in the Management of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized of cognitive dysfunction. AD is believed to be a global menace with an estimated fourfold increase in prevalence by the year 2050. This increasing prevalence is linked to the unavailability of efficient treatment to halt the disease progression. While several hypotheses have been postulated on AD, oxidative stress, a state of an imbalance between antioxidant and free radical generation, has long been implicated in the pathogenesis of age-dependent late-onset AD. This state induces cognitive decline by stimulating neuronal damage, notably involving increased free radical production, and mitochondrial dysfunction. Pharmacological agents used in AD management have serious adverse effects and inability to halt disease progression. This has led to the emergence of naturally occurring neuroprotective phytochemical agents and herbal supplements as therapeutic option agents. Indeed, emerging studies have revealed the neuroprotective potential of different African herbal products, containing bioflavonoid compounds with central nervous system permeability and high antioxidant actions. Given this background, this chapter aims to discuss some of these African antioxidant bioflavonoids\\nutraceuticals, their neuroprotective functions against different epigenetic-derived oxidative stress, and ways ahead to facilitate their translation from “bench to bedside” as primary intervention or co-adjuvant therapies for AD treatment.

1. Introduction

Alzheimer’s disease (AD) is a debilitating neurological disorder characterized by cognitive decline resulting from progressive neuronal death. AD is predominantly the most common form of dementia, notably increasing rapidly with prevalence of 2.3 to 20.0%, corresponding to an incidence rate of 13.3 per 1000 persons and a troubling mortality in different part of parts Africa [1]. Majority of cases of AD are diagnosed at age 65 years and above at a stage when it is referred to as a late-onset form of AD [1]. Symptom of AD begins with difficulty in remembering new information due to the loss of cells in the region of the brain such as frontal lobe, prefrontal cortex, and hippocampus, which are concerned with the formation and retention of new memories [2]. It is estimated that 6% of the aged population at 65 years are diagnosed with AD, and over 30% after age 85 years, while only 10% or less, below the age of 65 years may be diagnosed with the disease [3], although the latter age group is said to have early-onset AD [3, 4, 5]. With an increasingly aging population worldwide and epidemiological reports indicating an estimated fourfold rise in the prevalence of patients with AD, from 24 million by the year 2050 [6], there is an imperative need for early diagnosis and therapeutic intervention for this social-economic burdened disease [7]. This is pertinent as the cure for AD has so far remained unsuccessful due to lack of ability of orthodox drugs to halt the cause of the disease owing to incomplete understanding of the etiology of the disease.

There are four major pathogenic pathways that have been postulated to drive the etiology of AD, notably Aβ plaque formation (due to amyloid beta accumulation) [8, 9], protein misfolding, resulting from tau protein hyperphosphorylation [9, 10, 11, 12], cholinergic dysfunction as a result of hyperactivity of acetylcholinesterase (AChE) enzyme (a degradative enzyme responsible for acetylcholine – ACh, metabolism), as well as glutamate excitotoxicity, due to over-excitation of glutamatergic neurons [13, 14, 15, 16]. Central to the long-established pathogenic hypotheses of AD are the postulations of free radical-mediated neurodegeneration, oxidative damage, and neuroinflammation as possible culprits to the pathogenesis of the disease [17, 18, 19]. Oxidative imbalance is believed to cause an increase in the levels of pro-oxidant biochemicals in different organs of the body, including the brain, owing to low levels of antioxidant machinery and the presence of high amount of polyunsaturated fatty acids (PUFAs) [20, 21]. In the brain, oxidative imbalance causes an alteration in various brain enzymes including hyperactivation of the AChE activity [22]. Over-activation of the AChE enzyme notably depletes the concentration of ACh in the brain, the major neurotransmitter with prominent roles in learning and memory formation [23, 24]. Furthermore, oxidative imbalance is known to alter mitochondrial physiology and include one of the early events that initiates AD progression and promotion of cognitive decline [25].

Exogenous administration of natural and synthetic antioxidant supplements have been reported to hold promising beneficial effects to mitigate oxidative stress-derived neurodegenerative diseases such as AD [26]. Studies have shown that a higher intake of antioxidant supplements such as vitamins E, C, or a conjugate and dietary flavonoid over a 10-year period elicits significant reduction in the incidence of AD in elderly population of men and women [27]. This suggests that supplementation with antioxidants at the early onset of the disease may be an effective strategy to prevent or delay the disease and its progression [28, 29, 30]. However, despite the overwhelming evidence of the effects of antioxidants in AD pathology, the outcomes of antioxidant therapies have had limited clinical successes due to challenges such as poor blood-brain barrier (BBB) permeability and low levels of drug at the targeted site [31, 32]. To overcome such challenges would require a high dose of administration of the antioxidant supplements, which could, however, be toxic to humans [31, 32, 33, 34, 35]. In the last decade, however, several emphases have been given to the scientific characterization of the pharmacological effects of both naturally occurring and synthetic compounds, including the role of different delivery systems and nano-particles-based technologies to address the challenges faced in clinical translation [26].

Nano-systems made of polymers, lipids, or liposomes have been shown by different studies to offer therapeutic strategies for the delivery of neuroprotective antioxidant agents, thereby improving their BBB permeabilities and pharmacological properties [36, 37, 38]. For example, the levels of curcumin associated with nanostructured lipid carriers (NLCs) was increased in the brain and plasma of the AD mouse model compared to the levels of free curcumin [37]. The high bioavailability of the curcumin nanostructure produced a significant reduction in mitochondria oxidative stress and increased adenosine triphosphate (ATP) levels in the hippocampal tissue, thus improving cognitive impairment [37]. Hence, further preclinical and clinical studies are needed for the safety and risk profiling of nanotechnology-based phytochemicals as prophylactic agent for AD treatment. As further studies on the safety and risk profile of the nano-systems for anti-AD are needed, there is an urgent need for establishment of other neuroprotective compounds for AD treatment, owing to the rising cases of AD globally. Studies over the years have revealed the neuroprotective potentials of some African plants (polyherbal supplements and bioflavonoids), with high antioxidant constituents and CNS permeabilities, for the potential treatment of neurodegenerative diseases such as AD. This book chapter therefore provides evidence showing the possible involvement of oxidative stress in AD pathology, including the role of mitochondria dysfunction. Additionally, it also highlights the neuroprotective mechanisms of some African phytochemical compounds as therapeutic agents for the management of AD. Finally, the pharmacological properties including their therapeutic potentials, underlying mechanisms, and toxicological profile, of these agents were discussed in line with professional perspectives.

2. Oxidative stress and AD

Oxidative stress, which indicates a state of excessive reactive oxygen species (ROS) production, occurs when there is an imbalance in the levels of free radical generation and antioxidant protection [39]. The impact of this oxidative imbalance can be seen heavily on important cell components of the brain, causing metabolic peroxidation of lipids and oxidation of proteins and DNA/RNA [18, 40, 41, 42, 43]. Established evidence has shown that oxidative imbalance could lead to a shut-down of the brain’s antioxidant defense machinery such as catalase (CAT), glutathione (GSH), and superoxide dismutase (SOD), as well as other protective proteins [44, 45, 46]. Many reasons have been attributed to explain why the brain is one of the most vulnerable organs to the negative impacts of oxidative stress. These include (i) the presence of a high number of mitochondria loads and ATP generation in the brain, (ii) low antioxidant machinery, (iii) a high load of PUFAs and lipid-rich contents, (iv) the presence of vulnerable neuronal anatomic structures that are heavily dependent on oxygen, (v) the presence of oxidizable neurochemicals, and (vi) availability of redox transition metals and divalent ions such as iron and calcium [20, 21]. In line with this, oxidative stress-induced neuronal damage has a strong potential to cause or propagate neurodegenerative diseases such as AD.

Evidence gleaned over the years revealed that oxidative stress precedes other pathological mechanisms such as senile plague and neurofibrillary tangles formation in mild cognitive impaired (MCI) patients (patients who at the latent period of AD, prior to the appearance of symptoms of the disease) [47, 48, 49, 50]. Accordingly, markers of lipid, protein, and nucleic acids (DNA/RNA) oxidation were found in the plasma, urine, and cerebrospinal fluid of patients with MCI and early-stage AD. Thus, suggesting the role of oxidative stress in the pathogenesis of AD [51, 52, 53, 54, 55]. Furthermore, in age-dependent late-onset AD, oxidative stress has been confirmed to facilitate the production of Aβ peptides through up-regulation of β- and γ-secretases enzymes [56, 57, 58, 59, 60]. Cleaved Aβ further causes damage by inducing mitochondria dysfunction, which further increases the formation of free radicals, inhibits mitochondria ATP generation, and disrupts autophagic processes. Altered autophagic processes have been reported to induce the accumulation of senescent brain cells, a pathological pathway that is linked to a chronic state of oxidative stress [25, 61, 62]. Furthermore, it is also believed that disruption of mitochondrial homeostasis due to impaired autophagic processes could be attributed as one of the early events that exacerbate amyloidosis and cognitive decline in AD pathology [25].

2.1 The role of oxidative stress in mitochondria dysfunction and cognitive impairment

Neuronal mitochondria are the major organelles in the brain that are concerned with energy production and metabolism. The mitochondria are also responsible for other biological functions such as cell survival and death and regulation of calcium homeostasis [63, 64, 65, 66, 67]. However, due to the active oxidative metabolism that takes place in the brain by electron transport chain (ETC) of mitochondria, mitochondria are strongly implicated as a major source of ROS generation such as hydroxyl radicals (OH-), superoxide anion (O²⁻), and hydrogen peroxide (H₂O₂) (Figure 1) [68, 69, 70, 71] in the brain. Importantly, ROS are known to play a critical role in signaling functions as well as cytotoxicity, with their levels being kept in check by the cellular antioxidant defense system [72]. However, during the aging process, when mitochondrial function starts to decline [73, 74], as well as when the rate of ROS production exceeds the protective capacity of the innate antioxidant defense system, oxidative stress may damage important components of the cells, leading to oxidation of proteins, nucleic acids, and membranes [75]. Also, within the mitochondria, generated ROS could impair mitochondrial energy production by damaging mitochondrial DNA (mtDNA), leading to defects of the respiratory complexes in the mtDNA-encoded subunit [76, 77].

Figure 1.

Oxidative stress and lose of mitochondrial function in neurons cause the development of AD. ROS are typically generated via several mechanisms such as mitochondrial dysfunction (during the aging process), stress, and neuroinflammation. Excessive generation of ROS consequently leads to oxidative stress, which in turn causes mitochondrial dysfunction. Oxidative stress prevents the degradation of protein molecules (Aβ peptides) and prevents the clearance of misfolded tau proteins. This subsequently results in the aggregation of cytotoxic proteins, leading to neuronal death and impairment of cognitive functions due to alteration of synaptic plasticity. nDNA = nuclear deoxyribonucleic acid, mtDNA = mitochondrial deoxyribonucleic acid, H₂O₂ = hydrogen peroxide, NO₂ = nitrogen dioxide, NFT = neurofibrillary tangle, ER = endoplasmic reticulum, ⁻OH = hydroxyl ion, ⁻O₂ = oxygen radical, Aβ = amyloid beta.

Studies have shown that neuronal cells are particularly susceptible to mitochondrial ROS based on the continuous dependence of neurons on the ATP produced by mitochondria for excitability and neurotransmission [78]. This raises the possibility that the accumulation of oxidative insults within the cells can cause neuronal death, which is one of the drivers of AD pathology [78]. Therefore, documented evidence of early oxidative stress in neuronal mitochondria is linked to a decline in cognition.

2.2 Oxidative stress triggering factors and their effects on mitochondria and cognition

The delicate interplay between antioxidants and the generation of ROS can be compromised by exposure to environmental insults. Oxidative stress-mediated damage in tissues and cells is promoted by physical, chemical, and microbial agents. It is important to understand that oxidative-mediated reactions are crucial to many key aspects of life processes such as mitochondrial cell respiration, lipid synthesis, lysosome phagocytosis of foreign bodies (immunity and inflammation), and xenobiotic biotransformation of organic/inorganic compounds [79]. However, studies have reported that alterations in these biological processes, as well as excessive intake of substances, such as alcohol (e.g., ethanol) and certain food additives, are associated with up-regulation of oxidative processes and neuroinflammatory mediators that can facilitate the progression of AD [80, 81, 82].

Notably, ethanol intoxication induces cellular damage and neuronal death [80]. At the cellular level, ethanol impairs neurotransmitter signaling by altering glutamatergic and gamma amino butyric acid (GABA) inputs on parvocellular neurons of the paraventricular nucleus (PVN) of the hypothalamus [83, 84, 85]. This mechanism is responsible for chronic alcohol use disorder (AUD)-induced release of the stress hormone, cortisol/corticosterone, and the associated ROS generation. Of note, ethanol promotes ROS production in the developing cerebellum [86] and activates inflammatory and senescent neuronal processes due to the release of cortisol [87, 88]. Interestingly, mitochondrial oxidative stress appears to be the main mechanism to uncover ethanol-mediated neurotoxicity [88, 89]. However, mitochondrial dysfunction is dependent on the amount and duration of ethanol exposure, as observed in binge and chronic alcohol consumption, as well as in hangover and withdrawal states [88]. Ethanol-induced mitochondrial dysfunction has severe consequences on neuronal communication. This includes destabilization of the electron transport chain, thereby resulting in increased ROS production, alteration of mitochondrial respiration, and depletion of ATP production. Ethanol can also lead to the induction of cell death by opening the mitochondrial permeability transition pore (mPTP), as observed both in vitro and in vivo [88, 89].

Food additives, which are substances added to foods for the purpose of improving the quality of appearance and tastiness or as preservatives, are consumed by humans daily. Salts, brominated vegetables, vinegar, and monosodium glutamate (MSG) are some of the most widely known food additives. MSG is one of the most widely used food additives owing to its distinctive ability to enhance the flavor and savory qualities of foods [90]. MSG is generally considered to be safe by regulatory bodies; however, the lack of a fixed daily dose ratio in various preparations flooding the markets creates a disproportionate rate of consumption [91]. There are speculations that high consumption of MSG may facilitate the early formation of life-threatening diseases, especially on a chronic basis [82, 90]. Additionally, MSG has also been tagged excitotoxin or neurotoxin based on evidence of toxicity of several neuronal cells in the forebrain regions [92]. MSG-induced neurotoxicity is characterized by several symptomatic behavioral manifestations such as depression, anxiety, abnormal motor functions, and cognitive impairments [82, 90, 92]. Correspondingly, MSG impairs neuronal metabolism and causes abnormal generation of free radical moieties and inflammatory mediators [93].

3. African plants: polyherbal antioxidant supplements and bioflavonoids

3.1 Jobelyn®

Jobelyn® (JB) is an African polyherbal antioxidant nutraceutical derived from the leaf sheaths of Sorghum bicolor, commonly known as millet or guinea corn (Figure 2). Sorghum bicolor is an ancient plant that has been cultivated in North-eastern Africa for over 5000 years [94]. Historical uses of Sorghum include food, hot teas, beers, and trado-medicinal remedies [95]. It is also noteworthy to mention the fact that the West African variety of Sorghum synthesizes exceptionally high amounts of flavonoids in their non-grain tissue, the leaf sheaths [96]. The intensively colored leaf sheaths of this wild variety of Sorghum found within Nigeria have been formulated into a commercial pharmaceutical product under the name Jobelyn®. JB first gained public attention following its clinical efficacy in boosting hemoglobin contents and immune functions in patients with sickle cell blood disease [97]. JB consumption supports a healthy normalization of many aspects of blood cell production and function when administered at recommended doses [97]. Its strong anti-oxidative, immuno-modulatory, and multi-facetted anti-inflammatory properties have been used to treat and manage myriad diseases, ranging from cancer, diabetes, stroke, arthritis, and many other debilitating disorders [81, 98, 99]. Pharmacological investigations have also shown that JB exhibits neuroprotective properties including anti-amnesic, anti-depressant, and anti-psychotic effects [82, 98].

Figure 2.

Schematic diagram showing Sorghum bicolor seeds and plant.

3.1.1 Neuroprotective potency of Jobelyn® in animal models

The loss of cortical cytoarchitecture and neurons are implicated as contributing factors in the decline of cerebral functions following exposure to environmental insults and exogenous substances such as alcohol and food additives. There is no doubt that, in the quest to combat the menace of free radical assaults, it is critically important to identify agents that could provide an exogenous antioxidant system into the milieu interieur of the CNS to compensate for the endogenous depletion of antioxidants (Table 1) [97]. Accordingly, JB improved cognitive decline and showed anti-amnesic properties by diminishing oxidative insults, as evidenced by the profound suppression of malondialdehyde (MDA) levels, followed by elevated antioxidant defense armory, such as the increased concentrations of GSH in the brain of rodents [82, 100].

Therapeutic Agents	Animal Models	Mechanisms	Outcomes	References
Jobelyn®	Rat model of AUD	Reduces tissue destruction, oxidative stress, neuronal necrosis, and neuronal apoptosis in corticolimbic pathway.	Effective against neurodegeneration in AD	[81, 100]
	Rat model of AUD	Reduces oxidative stress and neuron-specific enolase immunoreactivity (NSE-IR) in the prefrontal cortex.	Effective against neurodegeneration in AD	[81]
	MSG-induced neurotoxicity in mice model	Attenuates memory deficit, hyperlocomotion, and increased oxido-nitrergic stress responses in brain and hepatic tissues.	Improves memory functions through the enhancement of cellular antioxidant machinery	[82]
	Scopolamine-induced amnesic rodents (mice and rat models)	Increases alternation behaviors by preventing formation of MDA and increasing the concentrations of GSH in the frontal cortex and hippocampus.	Improves memory functions and possesses anti-amnesic and antioxidant properties for AD treatment	[100]
Naringenin	Aluminum-induced neurotoxicity in rat model	Increases alternation behaviors. Reduces MDA levels and AChE enzyme activity. Increases the levels of SOD and CAT in rat brain.	Improves impaired cognition and offers neuroprotection against oxidative stress and cholinergic dysfunction	[101]
	Transgenic APPswe/PSΔE9 mouse model of AD	Inhibits GSK-3β activity and reduces senile plague.	Improves cognitive deficit through glucose uptake	[102]
	Ischemia-induced neurotoxicity in rat model	Increases mitochondrial phosphate, adenine nucleotide translocase transport activity, and membrane potential. Increases expression of Nrf2/ARE proteins in isolated neurons.	Reduces oxidative stress and improves mitochondrial dysfunction in neurons	[103]
Morin	Chronic unpredictable stress-induced mice model of AD	Enhances GSH levels, reduces MDA, and NO concentrations, and downregulates expressions of iNOS and NF-kB.	Reverses cognitive impairments in AD	[104]
	Aβ-induced AD cell models	Prevents neurotoxicity and enhances survival of neurons by reducing Aβ-induced toxicity, calcium overload to mitochondria, membrane depolarization, and release of cytochrome c in cortical neurons.	Restores mitochondrial function and redox homeostasis in AD via antioxidant mechanism	[105]
	The double transgenic APPswe/PS1dE9 mice	Inhibits Aβ production and plague burden. Decreased BACEI and PSI expression and facilitated Aβ degradation.	Restores cognitive functions and attenuates several neuropathological AD-like hallmarks	[106]
	MSG-induced neurotoxicity in rat model	Increased BDNF and Nrf2/HO-1 protein expressions. Decreases MDA, NF-kB, TNF-α, and IL1β levels in brain. Suppresses TLR4/NLRP3/caspase-1 pathways.	Offers neuroprotection against MSG-induced neuronal damage and dysfunction	[107]
Kolaviron	Scopolamine-induced neurotoxicity in rat model of AD	Increased levels of alternation behaviors. Attenuates lipid peroxidation, nitrite generation, and AChE enzymes in the PFC, hippocampus, and striatum of rat brain. Increased GSH and SOD levels.	Possesses cognition-enhancing effect through enhancement of antioxidant defense and cholinergic systems	[108]
	AlCl3 and NaN3-induced neurotoxicity in AD rat model	Inhibits aberrant oxidative redox reactions in mitochondrial machinery by normalizing neuronal glucose bioenergetics.	Reverses cerebellar neurodegeneration that underlies AD through oxidative redox and free radical scavenging properties	[109]

Table 1.

Phytochemicals in African plants showing promising neuroprotective effects.

Studies have revealed the mitigating potentials of JB against the neurotoxic effects of scopolamine [100] and attenuating effects against neurodegeneration initiated by chronic alcohol treatment in rodents [81]. Clinically, renowned medications (acamprosate, disulfiram, and naltrexone) for the treatment of AUDs targeted the psychoactive properties of alcohol, while the neurodegenerative effect of alcohol that drives alcohol-induced neurological dysfunction was not reversed by these agents [110]. Intriguingly, JB exhibited reductions in tissue destruction, oxidative stress, neuronal necrosis, and neuronal apoptosis in the corticolimbic pathway in rat models of AUD [81]. Furthermore, the anti-apoptotic effect of JB was reported to provide neuroprotection to environmentally-induced programmed cell death by maintaining neuronal survival via the control of tumor antigen p53 and ɤ-enolase regulated apoptotic and necrotic processes [111]. p53 controls the proliferation, chromosomal stability, and differentiation pattern of neural stem cells [112, 113]. Also, the protective effect of JB in AUD is plausibly associated with its anti-lipid peroxidative properties, as it reduces the level of MDA in the prefrontal cortex of rat brain tissues [81].

Amidst the diverse mechanistic actions that underlie MSG-induced neurotoxicity and hepatotoxicity in humans, agents with naturally occurring abilities and rich antioxidants, anti-inflammatory and neuroprotective activities, that could mitigate MSG’s neurotoxic insults, have been suggested to be of significant public health benefits. Interestingly, JB pretreatment attenuates the memory deficit, dysregulated hepatic enzyme function, serum protein contents, and cytoarchitectural changes in MSG-treated mice, suggesting hepatoprotective and neuroprotective functions. The beneficial effects of JB administration in mitigating the toxic effects of MSG include but are not limited to augmentation of the cellular antioxidant defense machinery [82, 90]. Additionally, JB reduced the severity of the devastating effects of human immunodeficiency virus (HIV) on the immune system and body organs including the brain, with improved neurocognitive activities in psychiatric patients, as well as in addressing the uncontrolled inflammation that causes tissue damage and pains in HIV-infected individuals [97].

3.2 Naringenin

The dietary flavanone glycoside naringenin, also known by its chemical name 4,5,7-trihydroxyflavanone (Figure 3), is largely found in citrus fruits including grapefruit and orange. Together with naringenin, naringin is a primary analog of naringenin which is responsible for the bitter taste of grapefruits [114]. The most common supplement source of naringenin and naringin is grapefruit seed extract, which is available in either capsules or liquid [115]. Importantly, naringenin serves as a typical example of a phytopharmaceutical agent. Studies have shown that naringin possesses diverse pharmacological activities and therapeutic potential for the treatment of a variety of diseases, including inflammation [62], cardiovascular disorders [62, 116], and metabolic syndrome [117], all of which elicit functional mechanisms that protect against neurodegenerative disorders such as AD [117]. Naringenin also acts as a potent antioxidant-free radical scavenging [118] and antistress compound against neurodegeneration induced by physical and psychological stressors [119].

Figure 3.

Chemical structure of naringenin.

3.2.1 Neuroprotective potency of naringenin in AD model

Neuroinflammation and oxidative stress are considered as causative factors of AD progression. Neuroinflammation derived from activated astrocytes and microglia (resident immune cells of the brain) hyperactivation is a typical hallmark of neurodegenerative diseases. Reports have shown that the activated form of these immune-competent cells is entangled with Aβ plaques in the brains of patients with AD [120]. Elevated secretion of cytokines such as interleukins (IL) and tumor necrosis factor-alpha (TNF-α) in the brain is believed to be a common feature of AD pathology [121]. Several studies found that naringin attenuates inflammatory factors such as transforming growth factor (TGF)-β1, IL-1β, TNF-α, and inactivated astrocytes and microglia in the hippocampus of AD animal models [122, 123, 124]. Furthermore, several studies have investigated the antioxidant properties of naringin by measuring the levels of ROS, SOD, reduced and oxidized GSH, CAT, and nitric oxide (NO) in animal models of AD resulting from chelating metals, with resulting improvement in mitochondrial function [101, 122, 123, 125, 126, 127, 128]. Also, naringin abated social defeat stress (SDS)-induced neuroimmune changes via mechanisms related to the inhibition of the release of pro-inflammatory cytokines (IL-6 and TNF-α) [119]. Thus, these findings suggest that modulation of neuroimmune cells by naringin could be regarded as an important mechanism to mitigate AD-related neuroinflammation. According to previous preclinical studies, most AD investigations are focused on biochemical markers that can be reviewed in four different levels, consisting of interaction with metals, change in AChE enzyme activities, protection against oxidative stress, and reduction in the extent of neuroinflammation [127]. Indeed, excessive amount of metal ions such as iron, selenium, copper, and zinc promote rapid aggregation of Aβ peptides, which are implicated in AD pathology. Therefore, agents with metal-chelating properties have been hypothesized to attenuate these detrimental effects [129]. Of note, metals are known to change the morphology of Aβ and promote Aβ aggregation in a neurotoxic manner [130]. However, many studies have revealed that naringin chelates excessive amounts of metal ions, including Cu²⁺, Fe³⁺, Al³⁺, Zn²⁺, and Mn²⁺, thereby preventing aggregation of Aβ peptides [101, 126, 131].

Since cholinergic neurons represent a crucial pathway in the central and peripheral nervous systems, in which it is implicated in cognitive function, enhancing the levels of ACh, through inhibition of AChE enzymes, is considered a viable strategy for the amelioration of AD-related cognitive decline [12, 132]. In line with this, naringin was reported to attenuate SDS-related cognitive decrement by enhancing cholinergic neurotransmission via inhibition of AChE enzyme activity [119]. Therefore, inhibition of AChE activity by naringin could be considered as one of the viable therapeutic strategies for mitigating AD [101, 122, 123, 128, 132, 133, 134, 135].

Furthermore, hyperphosphorylation of the tau protein causes a double-helical structural change that promotes the production of neurofibrillary tangles in AD pathology [136]. Tau protein phosphorylation is notably mediated by cyclin-dependent kinase 5 (CDK5) [137]. Interestingly, a recent study found that naringin lowered CDK5 expression, resulting in reduced tau protein phosphorylation [138]. Furthermore, naringin treatment boosted glutamate receptor-2 and N-methyl-d-aspartate receptor (NMDA)-1 expressions while decreasing calcium/calmodulin-dependent protein expression [138]. It is also believed that autophosphorylation of CaMKII inhibits long-term memory, a pathological mechanism commonly seen in patients with AD [139, 140]. However, Wang et al. reported that naringin improved CaMKII phosphorylation, elevated amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor phosphorylation, and improved the cognitive performance in transgenic mouse models of AD [131]. Additionally, mounting evidence also reviewed that naringin-treated mice exposed to hydrocortisone-induced memory impairment demonstrated memory-enhancing phenotype and increased neuroprotective markers, such as elevated expressions of B-cell lymphoma-2 (Bcl-2), Bcl-2 associated agonist of cell death (BAD) levels, as well as extracellular regulatory kinase proteins linked to mitogen-activated protein kinase (MAPK)/P38 pathways in the hippocampus [138]. Besides, Kaur and Prakash also established that naringin’s neuroprotective activities were mediated by modulation of NO signaling [126]. Indeed, elevated NO levels in AD models have been reported to be linked to elevated NF-kB levels in the hippocampus and cortical regions [141]. Naringin blocked the activation and translocation of protein kinase C, the consequent phosphorylation of IkB, and the reduction of NF-kB levels in the hippocampus and other cortical regions [123]. Aβ protein cleaving enzyme 1 (BACE1) diminishes amyloid proteins, thereby increasing Aβ production, which, in turn, causes excessive deposition of Aβ and nerve cell damage [142]. Meng et al. previously showed that naringin inhibits BACE1 expression, notably decreasing the content of amyloid protein and production of Aβ [138]. Thus, the findings from these studies suggest that naringin could be a promising anti-AD agent, given the variety of neuroprotective mechanisms.

3.3 Morin

Morin is a neuroactive polyphenolic compound obtained from the stem, fruit, and leaves of plants, especially of the Moraceae family [143]. Morin is obtainable from diverse sources such as guava, onion, almond, etc. Morin has been reported to be soluble in methanol, alcohol, water, acetic acid, and alkaline solutions (Figures 4 and 5) [13, 144, 146].

Figure 4.

Morin chemical structure (3,5,7,2′,4′-pentahydroxyflavone) [144].

Figure 5.

Diagram showing the diverse natural sources of Morin [145]. Morin is widely distributed in several fruits and vegetables including onion (Allium Cepa), oranges (Artocarpus Heterophyllus), and guava (Psidium Guajava), among others.

3.3.1 Neuroprotective potency of morin in AD models

Several studies have revealed the neuroprotective potential of morin in animal models of AD. Morin hydrate was found to offer a neuroprotective effect and improve cognitive impairments in mice exposed to chronic unpredictable stress [104] and sleep deprivation-induced memory deficits [147]. The results from the study showed that morin hydrate attenuates cognitive impairments by boosting endogenous antioxidant defense system through activation of GSH, reduction of lipid peroxidation marker (MDA), NO, and downregulation of iNOS and NF-kB expression in the hippocampus of mice brains, an important brain region involve in cognitive function.

In another study, morin hydrate offered neuroprotection to neurons by preventing mitochondrial dysfunction in Aβ oligomer-induced AD cell model [105]. Animal models involving neuronal cell death consequently leading to AD are known to be induced by Aβ-mediated ROS overproduction. Mitochondrial dysfunction by Aβ oligomer can also alter mitochondrial homeostasis by causing an increase in calcium overload and release of cytochrome c [148], which is linked to mitochondrial-dependent neuronal cell death [149]. Thus, attenuation of hippocampal neuronal cell death, evidenced by an increased population of pyknotic neurons by morin, has been reported to occur from augmentation of an endogenous enzymatic antioxidant system [22, 104]. These findings are suggestive of the promising potential of morin in the treatment of oxidative stress- and mitochondria-dependent AD progression. Elsewhere, morin prevented neurotoxicity in rats exposed to ifosfamide, a cytotoxic antineoplastic drug, by inhibiting AChE enzyme activities, reducing lipid peroxidation, depletion of GSH pool as well as stimulating the activity of nuclear erythroid-related factor-2 (Nrf2) and antioxidant enzyme system [150]. Elsewhere, doxorubicin-induced cognitive impairment [151] and psychotic-like behavior [22] that are associated with AD-like pathology were also dramatically reduce by morin via up-regulation of the GABAergic biosynthetic enzyme, glutamic acid decarboxylase-67 (GAD-67), brain-derived neurotrophic factor (BDNF), and inhibition of nicotinamide dinucleotide phosphate oxidase-2 (Nox-2) in the striatum, prefrontal cortex (PFC), and hippocampus of mice brains. Evidence showed that morin also modulates both monoaminergic and non-monoaminergic neurochemical pathways at the receptor levels to mediate memory enhancement as well as anti-depressant effects [152]. The study revealed that the memory-enhancing and anti-depressant-like effects of morin were reversible by pretreatment with cholinergic (atropine), 5-hydrotryptaminergic-2 (5-HT₂) (metergoline), α₁-noradrenoceptor (prazosin) and D₂ receptor (haloperidol) antagonists as well as 5-HT synthesis inhibitor (para-chlorophenylalanine) [152], nonselective NOS (nitro-l-arginine methyl ester, L-NAME) and selective neuronal NOS (methylene blue) inhibitors [153].

Moreover, morin exerted neuroprotective function against brain insults caused by MSG by targeting Nrf2/heme oxygenase-1 (HO-1) pathways and the inhibition of toll-like receptor-4 (TLR4)/Nod-like receptor protein 3 (NLRP3) inflammasome signaling pathways [107]. Given the anti-inflammatory function of the cholinergic system, which is mediated through alpha-7 nicotinic cholinergic receptors (α7nAChRs), previous studies have established that up-regulation of NLRP3 pathways and neuroinflammation can be mediated by conditions associated with cholinergic deficit [154]. The blockade of NLRP3 inflammasome was reported to inhibit the mitochondrial release of neurotoxic elements such as pro-oxidant anions, cytochrome c, and mitochondrial DNA into the cytoplasm of macrophage. This is believed to attenuate ATP-induced apoptosis and neuroinflammation, as well as other signaling proteins such as extracellular high mobility groupbox 1 (HMGB1) [154]. On the other hand, the actions of neuroprotective phytochemicals such as morin with cholinergic agonism activity include inhibition of neuroinflammation-mediated neuronal cell death [155]. Together, these findings raise the potential therapeutic benefits of morin against cholinergic deficit-mediated neuroinflammation in AD pathology.

3.4 Kolaviron

Kolaviron (KV), a biflavonoid complex largely deposited in the West African edible Garcinia kola seeds, is a very popular African biflavonoid widely used in the South-Western and South-South part of Nigeria due to its diverse pharmacological activities [156]. These activities include antioxidant [108], anti-inflammatory [157], anti-nociceptive [158], anti-diabetic and anti-hypercholesterolemic [159], antigenotoxic and hepatoprotective [160], gastroprotective [161], antimalarial and hematoprotective [162], renoprotective, cardioprotective, gonadoprotective [156, 163, 164], and neuroprotective [156, 165] functions. Biflavonoids belong to a subclass of plant flavonoids that accumulate in vegetal tissues, including leaves, roots, fruits, and seeds [166]. Structurally, biflavonoids comprised of two identical or non-identical flavone flavonoid units joined by a symmetrical or unsymmetrical manner through an alkyl or alkoxy-based linker of varying length [166]. Majority of the known biflavonoids exhibit anti-oxidative effects among other biological activities (Figure 6).

Figure 6.

Garcinia kola seeds.

3.4.1 Neuroprotective potency of Kolaviron

The intrinsic antioxidant and anti-inflammatory activities of KV offer a potential neuroprotective effect against oxidative imbalance in neurodegenerative disease such as AD. Dietary inclusion or supplementation [166], which includes administration of KV, was reported to prevent brain microstructural derangements in plastic brain areas, like the cerebellum, hippocampus, and cerebral cortex, in association with cognitive deficits, in rodents exposed to radiotherapy [167, 168], malnourishment, and chemical-induced neurotoxicity [169, 170]. Additionally, scientific investigations have confirmed that KV also confers neuroprotection that includes reversal of scopolamine-induced memory impairment [108]. While examining the consequence of KV supplementation, these findings remarkably suggest that neuropathological alterations within the PFC and hippocampus are mostly involved in the progressive cognitive decline associated with the clinical manifestations of AD [171].

It has been suggested that alterations in mitochondrial functions lead to compromised neuronal antioxidant system, dysfunctional neural bioenergetics, hypertrophic astrogliosis (which consists of hyperplasia and exaggerated astrocyte proliferation of damaged areas), cytoskeletal dysregulation, and neuronal death within the PFC and hippocampus. These degenerative events were associated with sodium azide (NaN3) and aluminum chloride (AlCl3) toxicities in rats [109]. Importantly, KV was reported to show neuroprotective functions within the cortico-hippocampal brain cells through multiple mechanisms, such as the up-regulation of antioxidant defense systems and pro-survival pathway, notably displaying a significant prophylactic activity and a regenerative potential [109]. In line with these observations, KV also acts as an AChE inhibitor in the hippocampal and striatal brain regions of adult Wistar rats, thereby remarkably unveiling its therapeutic potential in the management of neurodegenerative disorders associated with dysregulated cholinergic signaling [172].

Furthermore, as regards KV’s utility in the management of neurological disease such as stroke and its associated AD-like phenotypes, KV produced a remarkable ablation of ischemia/reperfusion [165, 173] injury-induced oxidative stress, neurochemical aberrations, and brain edema through the regulation of redox and electrolyte homeostasis, as well as anti-inflammatory and anti-excitotoxic mechanisms, in a two-vessel occlusion (2-VO) model of stroke in rats [173]. KV post-treatment reduced pro-oxidants and augmented endogenous antioxidant enzymes in the cortex, striatum, and hippocampus, which resulted in the attenuation of post-ischemic oxidative stress. It also attenuates neurotransmitter dysregulation by increasing dopamine level (via tyrosine hydroxylase optimization and monoamine oxidase suppression) and reduces hippocampal AChE activity of rat brain [165, 173]. Additionally, KV reversed post-ischemic excitotoxicity, membrane depolarization and ionic imbalance by inhibition of lactate dehydrogenase activity and optimization of Na⁺ K⁺ ATPase and glutamine synthetase activities. Brain injury mediated by 2-VO-induced mitochondrial dysfunction does not result from inhibition of mitochondrial ATP synthesis alone but also from the overproduction of ROS, notably induced by the blockage of mitochondrial complexes (Complexes I-III) during ischemia and reperfusion. Aside from the antioxidant properties, KV post-treatment attenuated post-ischemic mitochondrial dysfunction by boosting mitochondrial complexes II, I/III, and III/I activities, which apparently contributed to its energy-replenishing action [172]. Of note, KV amelioration of I/R-induced mitochondrial dysfunction may be achieved through the reduction of membrane swelling and the restoration of mitochondrial membrane potential and structural integrity [172]. Together, these findings provide insight into the role of ROS in the display of neurological diseases such as stroke and its associated AD-like phenotype related to cognitive impairment and the potential mechanisms by which KV exhibits neuroprotective functions.

Taken together, these findings indicate that KV exhibits neuroprotective effects, which may be beneficial for the prevention and management of AD via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.

4. Discussion: Important pharmacokinetic profiles and pharmacodynamic actions of African phytochemicals for management of AD

4.1 Jobelyn®

JB, as a dietary supplement, has shown outstanding oxygen radical absorbance capacity value (37,622 μmol/TE/g), the highest thus far recorded in any known plant [82, 174]. JB was also found to possess significant levels of antioxidant activities against peroxyl radicals (3549 μmoleTE/g), peroxynitrite (269 μmoleTE/g), hydroxyl radicals (18,387 μmoleTE/g), superoxide ions (11,417 μmoleTE/g), and singlet oxygen (4000 μmoleTE/g) [97]. JB was reported to possess a unique combination of several biologically active phytochemicals with potent antioxidant, anti-inflammatory, anti-aging, and neuroprotective properties [82, 90, 100, 175]. JB mitigates the neurotoxic effects of scopolamine [100] and attenuates neurodegeneration evoked by chronic alcohol treatment in rodents [81]. These effects were attributed to its rich flavonoid-based polyphenolic phytochemicals such as naringenin, luteolin, apigenin, luteolinidins, apigeninidins, and dimeric-3-deoxyanthocyanidin [82, 97]. Few studies are available about the lipophilic potential and BBB permeability of JB. However, it has been demonstrated that natural products including flavonoid-rich products like JB can traverse the BBB, based on their permeating lipophilic capacity. As established, the BBB is formed by the endothelial cells of the brain microvasculature, which are connected by tight junctions [176]. The high lipophilicity among the flavonoids, dock with p38MAPK, c-Jun N-terminal kinase, extracellular signal-regulated kinase (ERK1/2) signaling pathways in the brain [177] evidently suggest that JB molecule has a high probability of crossing the BBB for the management of AD. Interestingly, there have been no reported cases of adverse effects or allergic reactions of JB over the years (especially on the CNS), and acute as well as chronic studies revealed that it is well tolerated by laboratory animals [97].

4.2 Naringenin

Naringenin is commonly found in foods (citrus fruits and tomatoes), as a glycoside of naringin, hydrolyzed by intestinal bacterial and naringinase enzymes [178]. Intestinal absorption of naringenin has been found to quickly achieve a rapid bioavailability in circulation [179]. Naringenin is released in human urine and plasma after oral dosages of pure naringin or grapefruit juice, although with a low estimable detection limit due to its poor water solubility [180, 181]. However, because naringenin is lipophilic, it is probable that it accumulates within tissues, particularly membranes, and eventually reaches higher quantities than those detected in plasma [182]. Naringenin undergoes a rapid hepatic first-pass metabolism, which results in its limited bioavailability in plasma [180, 183, 184]. As per in vitro and in situ studies, naringenin has high permeability across the BBB [185, 186]. Besides, the long-term toxicological studies of naringenin revealed that naringenin was relatively safe with a low toxicity profile [187, 188, 189].

The effects of naringenin are generally known to be centered on anti-apoptotic effects, as well as antioxidant and anti-inflammatory activities (Figure 7) [190]. Naringenin stimulates gene expression of Nrf2 and its target genes, which are responsible for the inhibition or scavenging of ROS [191]. The Nrf2 is a basic leucine zipper protein and a redox-sensitive transcription factor in the cap’n’collar (Cnc) family [191]. Previous research has shown that Nrf2 and the antioxidant response element (ARE) pathway protect mammalian neurons against the formation of oxidative stress. Nrf2 is largely found in the cytoplasm and interacts with Kelch-like ECH-associated protein1 (Keap1) [192]. This Keap1/Nrf2 complex is destined for ubiquitination and proteasomal destruction, preventing Nrf2 activity [192]. In reaction to stress, Nrf2 is phosphorylated and liberated from Keap1 before translocating to the nucleus to carry out its transcriptional functions [193]. As a result, the discovery of novel compounds that control the Nrf2/ARE pathway may contribute to the development of new therapeutic options for oxidative stress-related disorders. According to some studies, naringenin reduces lactate dehydrogenase leakage and ROS formation, enhancing mitochondrial membrane potential, and reduces caspase-3/9 activity and DNA damage [103, 194, 195]. Moreover, naringenine provides anti-inflammatory activities by inhibiting TNF-α, ROS, INOS, and NF-κB, with collective effects against these three inhibitory pathways suggesting beneficial effects indicative of anti-AD potential.

Figure 7.

Mechanisms of naringenin, morin, kolaviron and Jobelyn® exploring anti-apoptotic, anti-inflammatory, and antioxidant actions. They exert their antioxidant effects by acting on the nuclear erythroid-2-related factor (Nrf2) and antioxidant response element (ARE) pathways. Their anti-inflammatory actions are is through the inhibition of tissue necrosing factor-α (TNF-α), induce nitric oxide synthase (iNOS), reactive oxygen species (ROS), interleukin-1, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Their anti-apoptotic activities are carried out through the reduction of caspase activity. The collective effects of these three inhibitory pathways function to provide an anti-AD effects of these phytochemical active agents.

4.3 Morin

Morin is a non-toxic bioactive phytochemical agent with broad pharmacological activities including antioxidant, anti-inflammatory, anti-diabetic, and anti-amyliodogenic effects. Interestingly, morin possesses good pharmacokinetic enhancing properties when co-administered with other drugs owing to its P-glycoprotein modulating properties [143, 196, 197]. This is suggestive of the use of morin as a co-formulant agent for pharmaceutical compounds to improve the absorption of drugs used in the treatment of AD [198]. Moreover, a study has established that morin has a low toxicity profile. Chronic administration of morin is well tolerated and devoid of deleterious side effects [143]. Morin has also been established to be pharmacologically beneficial for the management of cancer [199], diabetes [200], kidney damage [201], schizophrenia [22, 153, 202], and psychosocial stress [149]. Convincingly, these data suggest that morin possesses therapeutic potential beneficial enough for the prevention or treatment of AD-like manifestation [203].

One of the foremost ways phytochemical compounds exhibit neuroprotective functions against pro-oxidants and cognitive decline is through anti-oxidative and free radical scavenging activities. Morin was experimentally reported to demonstrate pharmacological properties, including neuroprotection, primarily via mechanisms linked to anti-oxidative and radical scavenging properties [22, 104, 114, 144, 202]. Morin is one bioflavonoid with high antioxidant and free radical scavenging potentials due to its rich chemical bonds and compositions notably including the presence of two hydroxyl groups (-OH) on 2′ and 4′ positions of the B ring structure, as well as the presence of double bond between C2 and C3 atom (Figure 4) [204, 205, 206]. By acting as a ROS scavenger, morin has demonstrated potency against neurodegenerative diseases such as AD [207] through a microemulsion technology [207]. Accordingly, morin’s anti-oxidative potency is popularly known to include a reduction of MDA and nitrergic levels and an increase in antioxidant enzymes machinery (GSH, SOD, and GPx) in rats [208] and mice [22, 104, 202]. Besides, morin is also established to up-regulate the Nrf2 signaling pathway, which is one of the most important regulatory pathways involved in the activation of endogenous antioxidant system [209]. Enhancement of the Nrf2 by morin is remarkably further linked to the neuroprotection and anti-neuroinflammatory property of morin in mice exposed to lipopolysaccharide (LPS), an endotoxemia agent used to mimic AD-like pathology linked to neuroimmune alteration [209]. Moreover, also Ben-Azu et al. [155] demonstrated that morin increases cortical neuron arborization via inhibition of release of pro-inflammatory cytokines and downregulation of NF-kB signaling. Given this background, these evidence clearly suggest that the pharmacological effects of morin against AD-like conditions might be strongly connected with the inhibition of neuroinflammation-mediated neurodegeneration.

4.4 Kolaviron

The antioxidant and free radicals-scavenging activities of KV have been amply reported. KV improved antioxidant status by enhancing antioxidant gene expressions and scavenging ROS in atrazine-induced cytotoxicity of rat Leydig cells [210]. KV also prevented lipid peroxidation and reduced the damages to proteins and lipids induced by Fe3+/EDTA/ascorbate mixtures [211]. Moreover, KV inhibited intracellular ROS production caused by hydrogen peroxide in human hepatoma (HepG2) cells in a dose-dependent pattern [212]. Moreover, KV protected against oxygen-derived radical-induced DNA damage and oxidative stress in human lymphocytes and rat liver cells [161]. Additionally, KV administration was found to normalize kidney and liver antioxidant enzymes (SOD and CAT) and stabilize nonenzymatic antioxidant (GSH) levels, notably showing protective effect against ROS overproduction induced by diclofenac in the kidney and liver of rats [213]. KV reversed busulfan-induced neuroendopathobiological derangements via oxidative stress inhibition, downregulation of inflammatory and apoptotic mediators, as well as neurochemical modulations in rats’ teste–brain axis [156]. KV also reduces oxidative stress and tissue damage by inhibiting the rate of lipid peroxidation and production of oxygen radicals. This is important in limiting oxidative tissue damage in neural tissue, which is usually due to the selective susceptibility of the neural cells to ROS created during a dysregulated energy metabolism process [214]. Furthermore, activation of macrophage treated with KV by LPS resulted in phosphorylation of Akt, while ERK1/2, IkB, and NF-kB (p56) were inhibited without affecting cyclic response binding element, when mitochondria were used as a target for safety and toxicity studies of phytochemicals [215]. This finding also re-establishes the anti-inflammatory mechanism of KV in neurodegenerative diseases involving mitochondrial dysfunction, such as AD. The long-term toxicology profile of KV revealed that KV is considerably safe, with some variations in response between female and male animals [216]. A 90-day oral toxicological profiling revealed that KV is relatively safe and possesses lipid-lowering, erythropoiesis-enhancing, and immune-boosting effects (Table 2) [216].

S/N	Phytochemical agents	Mechanisms of action	Therapeutic potential	BBB permeability	Toxicity
1.	Jobelyn®	Antioxidant: increases catalase and glutathione [82, 100].	Anti-amnestic and anti-depressant effects; Improve neurocognitive activities in psychotic-induced mice; Attenuates neurodegeneration; Diminishes oxidative insults; Reduction in tissue destruction, neuronal necrosis in cortical limbic pathway	Crosses the BBB	No reported cases of adverse events or allergic reactions [97]
		Anti-inflammatory: Inhibit ROS, TNF-α, NF-kB [100].
		Free radical scavenging: Possess free radical scavenging activities against superoxide, hydroxyl, and oxygen radicals [97].
2.	Naringenin	Antioxidants: Promote moiety of Nrf2/Keap1 to produce antioxidants [118].	Decreases myocytes necrosis; Exerts cytoprotective effects; Immune booster	Permeable across BBB [185, 186]	Low toxicity profile [187, 188, 189]
		Anti-inflammatory-: it inhibits COX-2, PGE2, TNF-α & ROS.
		It possesses free radical scavenging activity.
3.	Morin	Antioxidants: Promotes moiety of NrF2/Keap1 to produce antioxidants [118, 209].	It attenuates neurotoxicity effects.; Possesses neuroprotective effect		Low toxicity [143]
		Anti-inflammatory: it inhibits TNF-α and ROS.
		It possesses free radical scavenging activity.
4	Kolaviron	Antioxidant: It improves antioxidant gene expression [108].	Promotes neuroprotective effects; Maintains integrity of the neurons; It prevents brain microstructure derangements		Low toxicity profile [216]
		Anti-inflammatory: Inhibits ROS [160].
		Possesses free radical scavenging just to prevent lipid peroxidation.

Table 2.

Pharmacological proprieties of phytochemicals present in African plants.

5. Future perspective

Natural plant products have recently gained enormous attention in drug research and development for disease treatment due to their availability and safety profile. Several natural medicinal supplements are now available in the market. Pharmacological interventions based on the use of phytochemical agents from African plants (as supplements or drugs) have presented a promising therapeutic opportunity for the management several disease conditions including AD. Several beneficial reasons, which include but are not limited to BBB permeabilities and low toxicity profile, are some of the neurotherapeutic barriers effectively overcome using phytochemicals as neuroprotective agents for the treatment of AD. However, the use of phytochemicals as anti-AD interventional agents still have several limitations. One of such is the challenge of toxicity assessment profile of these agents, especially on the CNS. Investigations have focused more on efficacy and, mostly, on preclinical studies involving animal models. Moreover, in the face of the promising preclinical studies involving the use of nano-systems, made of lipid or polymer, as carriers in the delivery of neuroprotective agents for late-onset AD, certain challenges must also be overcome before these nutraceutical agents can be fully beneficial. Induction of oxidative stress and inflammation have been shown to be the major mechanisms of nanotoxicity for nanoparticle-based delivery agents. This implies that in a susceptible population with weaker anti-oxidative and immune functions, such as the aged population of patients with AD, nanotoxicity associated with nano-based therapeutics may be exacerbated. In this regard, future studies should be on ways to mitigate nanotoxicity associated with nano-based therapeutics and the use of more primate animal model for studies.

There have been many preclinical experiments showing the neuroprotective potentials of African plants [217, 218, 219, 220, 221, 222, 223, 224, 225, 226], but there have been no clinical trials for the agents. Therefore, future studies of these medicinal agents may present contrasting results in biological systems in the form of low catalytic activity in the CNS compared to preclinical and in vitro studies. In the near future, the use of phytochemicals as anti-AD agents may result from evaluating catalytic, safety, as well as the efficacy profile of these agents in human studies. In this regard, it can be said that human studies would be needed to translate the existing preclinical findings on agents into clinical use as anti-AD agents. For example, previous research findings from clinical trials on JB suggest that JB provides promising results against the neurocognitive declines in patients with HIV. In future, in-depth knowledge to understand the mechanism by which JB offers this therapeutic benefit against neurocognitive decline in patients living with HIV would be highly imperative.

Furthermore, the clinical translation of AD has become challenging due to a lack of proper understanding of the pathogenesis of the disease. The lack of proper animal models for preclinical studies to facilitate the provision of predictable data for clinical studies is one key limitation. Therefore, the successful development of AD therapeutics would involve the development of better animal models for preclinical studies. Also, in the future, the development of high-throughput extraction and isolation techniques for African plants will be required to improve the quality of isolates that are needed for preclinical screening and studies. Of note, this would require the involvement of pharmacometric experts to mathematically model the biology, pharmacology, and disease progression of AD and drug treatment. This may help to facilitate an understanding of the interactions between environmental stimulants such as stress, diets, and pollution in the etiology of AD, as well as increase the predictability of beneficial and harmful outcomes of these African phytochemicals.

Additionally, it is important to put into consideration the pharmacodynamic and pharmacokinetic characteristics of phytochemicals before administering. The high anti-oxidative constituents of these agents may raise concerns about potential toxicity due to dosing. Therefore, thoroughly researching the optimum dosing regimen of the drugs as well as the stage to initiate treatment would help to improve the outcomes of clinical studies. The potentials of these phytochemical agents in the pharmacological defense against oxidative stress-mediated factors and neuroinflammatory mediators, especially in the mitochondria, have already been discussed. However, not so much was discussed about the potentials of the African plant compounds in maintaining the brain energy metabolism. Only a few of the available data have this included. Future investigations would be needed to focus on understanding how the African plant compounds maintain the brain energy metabolism in normalizing mitochondrial functions and ameliorating cognitive decline.

Moreover, it is important to understand that excessive consumption of exogenous substances such as alcohol and food additives are some of the contributing factors that initiate cognitive declines due to impaired neurogenesis of cortical and limbic regions via mechanisms linked to oxidative damage and neuroinflammation. There is evidence of food additives, such as MSG, in food products (especially for infants) above the daily limit recommended dosage by the World Health Organization. This is an indication that exposure of the CNS to oxidative damage possibly occurs even at an early age and is one of the drivers of neurodegeneration and premature aging. Interestingly, studies have shown that supplementation with antioxidants at the early onset of the disease may be an effective strategy in preventing AD and its progression. The potentials of the African phytochemical plants in rendering neuroprotective effects to the brain against oxidative-mediated neuronal degeneration have been discussed. However, the translation of this powerful dietary supplement as a co-adjuvant or to fortify food products, to mitigate neurotoxicity, was not included. Future research is therefore recommended to focus on ways to promote the incorporation of antioxidant supplements into food products, to mitigate their influence in altering oxidative stress, neurochemical neurotransmissions, and neuronal degenerations as well as to prevent the occurrence of cognitive decline over time.

6. Conclusion

Neurodegenerative disease like AD is fast becoming the world’s disease burden that encompasses disabilities affecting the brain cognitive abilities of sufferers. Aging, lifestyle, and environmental degradation evoking neuronal oxidative imbalance have been postulated as a possible cause of CNS disorders like AD. Neurotoxicity and physiological barriers of the BBB have posed some of the hurdles to drug treatment of AD. The use of natural plant products with anti-oxidative constituents may, however, be helpful to neuronal derangements, as they offer superior medicinal functions and lesser toxicity compared to conventional drugs. The current demand for effective intervention for AD is concentrated on the neuroprotection of neuronal cells from oxidative damage. Some African plant products, with CNS permeabilities and low toxicity, were found to treat neurodegenerative disorders like AD and offer neuroprotection against Aβ oligomers, ROS generation, and mitochondrial dysfunction (Table 1). The African plants were found to restore cognition and mitochondrial function in animal models through their competent anti-oxidative, free radical scavenging, and anti-inflammatory properties.

The use of natural plant products as supplements or formulations may completely alter how AD therapeutic interventions are addressed because of their abilities to permeate the BBB and offer neuroprotection, with little or no adverse effects. Although it can be said that this may open new therapeutic strategies or targets in the intervention of neurodegenerative diseases including AD, more studies involving humans are needed to translate their use from bench to bedside. This is with the objective of significantly reducing the cases and social-economic burden of AD.

Conflict of interest

None.

Author contributions

AMO and BB-A conceptualized the chapter. AMO, BB-A, BO, and EOC wrote the manuscript. BB-A edited the chapter. All authors approved the submission of the chapter.

Funding

This research was supported by the Canadian-Israel Research grant aided by the Canadian Institutes of Health Research (CIHR), the International Development Research Center, the Israel Science Foundation, and the Azrieli Foundation awarded to BB-A at Delta State University, Abraka.