Ion Channels and Neurodegenerative Disease Aging Related

Abstract

Many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and age-related disorders are caused due to altered function or mutation in ion channels. Ion channels are important in maintaining cell homeostasis because they affect membrane potential and play a critical role in neurotransmitter secretion. As a result, it appears that a potential antiaging therapy strategy should consider treating multiple diseases at the same time or focusing on identifying a common target among the biological processes implicated in aging. In this chapter, we will go over some of the fundamental ideas of ion channel function in aging, as well as an overview of how ion channels operate in some of the most common aging-related disorders.

1. Introduction

Aging is a natural part of life that comprises both physical and mental changes. In distinct organs, aging occurs at molecular, cellular, and histological levels, including in the central nervous system (CNS) and specifically in the brain [1, 2]. The molecular, chemical, and physical properties of neurons change as we become older, resulting in memory loss, altered behaviors, loss of cognition functions, dementia, and reduced immunological responses. In addition, aging is a major risk factor for neurological diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and others. Although the basic reasons of aging are unknown, there is widespread agreement that its etiology is multifaceted [3]. Aging theories can be classified into two categories: those that explain aging as the outcome of damage accumulation and those that explain aging as the result of controlled death processes [4]. It is likely that the interaction of these two basic systems influences the aging process, albeit there is a lot of variation across people. Two of the most accredited molecular alteration involved in brain aging are inflammation and oxidative stress that, when happen lead to cells failure. Different studies reported that reactive oxidative species (ROS), and subsequent oxidation of proteins, involved also ion channels [5].

Ion channels are integral membrane proteins that allow the passive diffusion of ions across membranes [2]. In neurons and other excitable cells, the harmonious coordination between the numerous types of ion channels shapes and propagates electrical signals [6]. Understanding the biology of aging mechanisms is essential to the pursuit of brain health. The ability to stratify senior populations and forecast clinical trajectories in pre-symptomatic adult groups could be critical to the future of aging research [4]. In this chapter, we will discuss about the role of ion channels in the brain during aging with particular attention on neurodegenerative disease age-related. Additionally, we will consider if ion channels could be used as future therapeutic targets to decelerate brain aging and age-related pathologies.

2. Brain aging: from physiological to pathological

Scientists have been debating the meaning of aging for a long time. Many people regard aging as an illness in and of itself, while others see it as the gradual loss of function that increases the risk of developing age-related diseases. Scientists view aging as an adaptation to lifelong events, and interventions should support the physiological balance during age-related adaptation, response to acute stress, to avoid disease onset. Adapted capacity in most organs has been shown to occur from the third and fourth decades of life [4]. Aging is a complicated and multifaceted condition marked by a steady decline in physiological and behavioral abilities. Aging happens in all organs at all levels, in the brain [2]. The molecular, chemical, and physical properties of neurons change as we become older, resulting in memory loss, altered behaviors, loss of cognition functions, dementia, and reduced immunological responses. Rather than significant rates of neuron loss, brain aging has been linked to subtle changes in the structure and function of neurons in specific neural circuits. The aging brain compensates for the loss of neurons by growing dendritic arbors and synaptic connections. Dendritic arbors and synaptic connections are lost in the brain in age-related neurodegenerative disorders. As a result, it is unable to compensate for the loss of neurons [7]. Synaptic degeneration, dendritic regression in pyramidal neurons, deposition of fluorescent pigments, cytoskeletal abnormalities, a reduction of striatal dopamine receptors, and astrogliosis and microgliosis are all prevalent features of brain aging in mammals [8]. Despite the discovery of brain aging characteristics in multiple neural networks, the chemical pathways responsible remain unknown [9]. Oxidative stress, inflammation, and ion channel failure are the most widely accepted theories for the development of age-related neurodegenerative diseases [10].

2.1 Oxidative stress in brain

In the 1950s, Harman’s free radical theory of aging suggested that reactive oxygen and nitrogen species (ROS and RNS) cause oxidative damage in cellular macromolecules, including DNA, proteins, and lipids, leading to decreased biochemical and physiological function through aging [11]. The changes in phospholipid composition show that ROS-induced lipid peroxidation occurs in the brains of elderly humans and animals with CNS dysfunction, such as cognitive impairment. Furthermore, increased formation of malondialdehyde (MDA) in the brain has been postulated as a symptom of aging [12]. Superoxide anions produced by the respiratory chain and various oxidases, hydroxyl radical created by the hydrogen peroxide interaction with Cu⁺ or Fe²⁺, and NO produced in response to elevated intracellular Ca²⁺ levels are just two of the most common examples of ROS in neurons [13]. During brain aging, enhanced ROS generation and decreased antioxidants result in redox imbalance, causing age-related disorders. NO-dependent oxidative damage promotes apoptosis in motor neurons. It causes vascular cognitive impairment through the aging of the cerebral cortex [14]. The action of several enzymatic and non-enzymatic systems with cellular detoxification functions, collectively referred to as antioxidants, mediates the hemostasis of intracellular ROS and RNS. The nuclear factor erythroid 2-related factor 2 (Nrf- 2) is the main transcription factor and one of the primary regulators of the antioxidant signaling, such as transcription of endogenous antioxidant enzymes including glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and heme oxygenase-1 (HO-1). This antioxidant system is collectively the primary defense system that neutralizes ROS generation inside the cells [15]. Additionally, another major antioxidant defense complexes are the heat-shock response (HSR), a cellular response that elevates the number of molecular chaperones to diminish the adverse effects on proteins caused via stressors, oxidative stress, increased temperatures, and heavy metals. Increased stress tolerance and cellular protection against neuronal injury can be achieved by activating heat-shock protein (HSP) synthesis [16]. As a result, in metabolic disturbances such as age-related neurodegenerative diseases and aging, the heat-shock response plays a critical role in creating a cytoprotective environment [2].

2.2 Inflammation in brain

Another key pathway directly involved in brain aging is represented by inflammation. The immune system is one of the most pivotal protective physiological systems of the organism [17]. Immunosenescence is a concept that describes how aging affects the immune system’s function [18]. The participation of senescent cells in host immunity is associated with the release of pro-inflammatory cytokines. This phenomenon is defined as senescence-associated secretory phenotype (SASP). Due to SASP’s pro-inflammatory tendency, cellular senescence in various organs and tissues significantly increases inflammation in the aged [19]. NF-κB in response to oncogenic stress and DNA damage initiates the transcription of a host of genes including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, IL-1β over stimulating SASP [20]. NF-κB is a transcription factor that is induced by inflammatory mediators and reactive oxygen species (ROS) and contributes to both detrimental and protective responses, depending on the types of induction that lead to the co-activation of distinct pathways. In addition, NF-kB activates genes that control cell survival, specialization, inflammatory processes, proliferation, and apoptosis [20]. It has been shown that the age-induced increase of pro-inflammatory markers (CRP, IL-6, IL-1β, TNF-α) is associated with cognitive decline [21]. Microglia are the brain resident macrophages providing its innate immune defense. Microglia, a kind of glial cell, arise from erythro-myeloid precursors in the yolk sac, which inter the CNS during development [22, 23]. In the neurological system, microglia play two roles. Microglia are ramified cells with extremely motile processes that continually scan the brain parenchyma in reaction to hazardous substances, neuronal cell damage, or infections in a healthy adult brain. Microglia have a dual function in the aging process. Microglia, on the one hand, release trophic factors and control cytokines [24, 25]. On the other hand, microglia enhanced amounts of an intricate set of mediators, such as TNFα, TGFβ, and IL1β, which are enhanced in elderly individuals [22, 23]. There has been evidence of a link between neuroinflammatory activation of microglia and neuronal loss, as well as impaired neurobehavioral function and cognitive impairment. Redox sensors found in receptors, transcription factors, and enzymes provide complex communication with oxidizing agents during neuroinflammation. These variables have an impact on the link between neurons and glia, as well as neuronal function, which leads to neurodegenerative alterations [26, 27]. Microglial cells also express a stimulable type of NOS following activation and produce large quantities of NO, which causes oxidative damage to neurons. In neurodegenerative illnesses and brain aging, improper immune cell activation causes functional impairment and synaptic degeneration; when properly controlled, these same cascades play critical roles in neuronal stress tolerance and neuroplasticity. For instance, TNF-α plays a pivotal role in learning, memory, and synaptic plasticity in the hippocampus [28]. Also, astrocytes may potentially play a role in adapting to age-related neuronal stress. These cells clear glutamate from synapses, produce neurotrophic factors and boost neuronal bioenergetic activity. Aging may decrease these astrocyte activities, hence, exacerbating pathogenic neuroinflammatory processes [28, 29, 30]. TNFα activates NF-κB which protects cells against neurotoxicity β-amyloid (Aβ)-induced and this activation is required for neuronal survival. NF-κB also promotes anti-apoptotic responses and protects neurons from ischemia and excitotoxic brain injury [31, 32, 33, 34, 35, 36]. Furthermore, through its response to TNF-mediated inflammatory stimuli, NF-κB activation plays a critical role in the start and persistence of inflammation, resulting in the stimulation of various chemokines and cytokines [37, 38, 39, 40, 41, 42].

3. Ion channels in the brain: from function to dysfunction

Ion channels are key components of neurons that are responsible for nerve impulse and synaptic transmission triggering (neurotransmitter’s release). These channels are divided into two big classes: (I) voltage-gated (Na⁺, K⁺, Ca²⁺, Cl⁻) and (II) ligand-gated (nicotinic acetylcholine receptors (nAChRs), γ-amino butyric acid (GABA), N-methyl-D-aspartate receptors (NMDARs), ryanodine receptors (RyRs)) that are involved in impulse transmission across the synapses [43]. However, during the last several decades, research has found a number of genetic faults or aberrations in channel-forming genes that are linked to a variety of neurological illnesses, including memory loss, movement difficulties, and neuromuscular disorders [44].

Ion channel protein establishes a pathway for ions such as Na⁺, K⁺, Ca²⁺, and Cl⁻ to flow across the lipid bilayer’s impermeable barrier [45]. They are known to play three main important functions in regulating membrane physiology: first of all, they set up membrane potential in cells, in which ion movement across the membrane creates a potential gradient that determines resting potentials and generates action potentials; secondary they are involved in the transmission of electrical signals; they are also involved in maintaining electrolytic balance across the cell membrane to regulate cell volume, and last but not least they play a crucial role in the generation of regulatory signals in the cell [46, 47]. Thanks to alternative splicing, their enormous structural variety from monomeric to heteromeric levels support their large functional diversity. The amplitude and duration of the action potential are shaped differently by each cell type’s assembly of ion channels [48, 49]. At the intracellular level, ion channels are also present on the surface of the mitochondria, endoplasmic reticulum, and nuclear membrane [50, 51]. The correct functionality of ion channels is necessary to keep physiological homeostasis in the brain [52].

As a result, ion channels have been implicated in a number of age-related dysfunctions [53]. Because aging is associated with physiological changes in ion channel function, aberrant changes in ionic gradients seem to be the core of age-related deterioration in physiological functioning. With age, functional changes in ion channels lead to clinical phenotypes called channelopathies [54].

3.1 K⁺ channels

K⁺ channels are the most ubiquitous and heteogeneous family of ion channels expressed in excitable and non-excitable cells (an extensive review on this topic can be found in [55]). K⁺channels can be divided into four classes: inwardly rectifying K⁺ channels (Kir), voltage-gated K⁺ channels (Kv), two-pore K⁺ channels (K2P), and Ca²⁺-activated K⁺ channels (KCa) [56]. K⁺ channels serve an important physiological function in the signaling mechanisms that lead to neurotransmitter release in neurons. They modulate the resting membrane potential, the repolarization phase of the action potential, and the firing frequency to govern neuronal excitability. Given the importance of K⁺ channels in so many cellular functions, it’s no surprise that changes in their activity have been linked to the development of a variety of neurodegenerative diseases [57, 58]. Furthermore, in recent years, it has been demonstrated that the apoptotic process, which is the key mechanism for cell selection and death in the CNS associated with physiological aging as well as a variety of neuropathological disorders, is critically dependent on changes in ion homeostasis within neuronal cells [59]. K⁺ efflux, which results in a drop in intracellular K⁺ concentration, maybe a key cause of apoptosis. In fact, in various neuronal populations undergoing apoptosis, an increase in outward K⁺ currents have been seen as well as it has been demonstrated that apoptosis has been shown to be inhibited by voltage-gated K⁺ channel blockers, whereas heterologous production of inwardly-rectifying K⁺ channels has been shown to increase apoptosis in cultured hippocampus neurons [60].

3.2 Ca²⁺ channels

Ca²⁺ is the major trigger of neurotransmitter release, a process that has been thoroughly investigated over the past decades [61, 62, 63]. Moreover, it has also become clear that Ca²⁺ is essential for a variety of other neuronal functions, including neuronal excitability, integration of electrical signals, synaptic plasticity, gene expression, metabolism, and programmed cell death [64]. Given its central role in processes that are fundamental to the excitable nature of neurons, Ca²⁺ homeostasis is tightly regulated in these cells. Plasma membrane Ca²⁺ channels allow the passive influx of calcium ions down their electrochemical gradient. These channels are divided into two groups based on the mechanism that controls their transition between open and closed conformations: voltage-gated Ca²⁺ channels (VOCC) and ligand-gated Ca²⁺ channels. The potential contribution of altered Ca²⁺ homeostasis at least to some aspects of brain aging and neurodegeneration was first put forward by Khachaturian in the 1980s, with the formulation of the “Ca²⁺ hypothesis of aging” [65, 66, 67]. Early findings in the field that corroborated this hypothesis examined the major transport pathways of Ca²⁺ during aging and found that at least in some types of neurons, such as the principal cells in the hippocampal CA1 region, there is an increased Ca²⁺ influx mediated by increased VOCC activity in aged neurons [68]. Similarly, Ca²⁺ extrusion through the ATP-driven plasma membrane Ca²⁺ pump (PMCA) was found to be decreased in aged neurons [69]. Following that, the attention switched to the intracellular mechanisms of Ca²⁺ homeostasis and how they degrade with age. The increased release of Ca²⁺ from the endoplasmatic reticulum (ER) stores via both the inositol 3-phosphate (InsP3) and ryanodine receptors (RyR) has been confirmed in several investigations, leading to the suggestion that release from the RyR receptor might be a valuable biomarker of neuronal aging [70]. The high influx of calcium ions into the postsynaptic spine appears to be the crucial event leading to the induction of long-term potentiation (LTP), which is relevant to the function of Ca²⁺ dysregulation in memory loss. Importantly, LTP is inhibited by intracellular Ca²⁺ chelators, whereas LTP is promoted when the postsynaptic cell is Ca²⁺-loaded [71]. Therefore, it is well established that a significant elevation of postsynaptic Ca²⁺ concentration is both necessary and sufficient for the induction of hippocampal LTP [72]. Ca²⁺ homeostasis changes may be directly responsible for neuronal death in some circumstances. Increased intracellular Ca²⁺ levels can cause severe abnormalities in neurons, eventually leading to neuronal death and degeneration [73]. This process is often specifically mediated or even initiated by the diminished capacity of mitochondria to buffer Ca²⁺. Given the basic relevance of Ca²⁺ homeostasis in the biology of all cells, it’s not unexpected that a growing number of studies demonstrate that unregulated Ca²⁺ plays a role in normal aging as well as a variety of pathological disorders. Given the nervous system’s incredible cellular variety, a general message emerging from this research is that Ca²⁺ signaling and homeostasis in the nervous system should be investigated. The Ca²⁺ homeostasis mechanism is equally variable across neurons, according to the demands of each neuronal subtype [62]. The intrinsic variations in morphology, connectivity, proteome, and Ca²⁺ homeostatic mechanism of neurons, taken together, are extremely likely to contribute to the selective sensitivity of diverse neuronal populations to different causes of senescence collectively and synergistically. The more we learn about how Ca²⁺ homeostatic processes interact with distinct neurons’ inherent properties, the closer we will be to devising cell-specific therapeutics [62].

3.3 Na⁺ channels

Voltage-gated sodium channels (Nav channels) are fundamental for the origination and transmission of signals in electrically excitable tissues. Na⁺ channels are abundant in neurons and glia throughout the central nervous system and peripheral nervous system (PNS) [74]. The genesis of neurological disorders, including as idiopathic epilepsy, ataxia, and pain sensitivity, is heavily influenced by mutations in genes encoding Na⁺ channels [75]. This is most likely due to changes in the synthesis and/or trafficking of Nav channels, which modify their surface expression and impact the neuron’s electrical excitability even while the channel’s conducting properties remain unchanged. Changes in the function of voltage-gated Na⁺ channels have been observed during the aging process [76]. These alterations were attributed to an age-related reduction in excitability, which is controlled by voltage-gated Na⁺ channels. Furthermore, age-related changes in voltage-gated Na⁺ channel activity have been proposed as a possible explanation for the decreased excitability seen in skeletal muscle fibers of old rats [77]. Considering the fundamental role of Nav channels in the modulation of neuronal responses during pathophysiological conditions, and the fact that RNS and ROS may play a role in neurodegenerative events, the study of Nav channel modulation by these free radical species assumes a particular pathophysiological relevance. Recent evidence shows that oxidant-induced alterations in the characteristics of Nav channels may play a role in membrane excitability and conductance modulation. Na⁺ currents were also elevated when NOS was inhibited or NO• was scavenged by hemoglobin and ferrous diethyl thiocarbamate. These findings suggest that RNS may act as autocrine regulators of Na⁺ currents in these neurons, inhibiting them. NO•, on the other hand, could potentiate the inactivation resistant Nav channels currents (INaP) seen in hippocampus neurons and posterior pituitary nerve terminals [1, 13, 78]. The current carried by these channels appears to be increased not only by the significant rise in NO• levels evoked by NO• donors but also by the lesser increase triggered by constitutive NOS activation [1, 13]. In hippocampal and pituitary neurons, NO• can cause an increase in Na⁺ currents, but it has the reverse effect in peripheral neuronal cells. As a result, it appears that NO• might have either neuroprotective or neurodegenerative effects due to its dual effects on various neuronal sodium channel populations. These effects are probably due to the variety of Nav channel subtypes expressed in the CNS and PNS.

4. Ion channels and neurodegeneration

Ion channel deficiencies and/or mutations relate to many forms of neurological diseases. Na⁺, K⁺, Ca²⁺, and Cl⁻ channel subtypes, for example, have been connected to the pathophysiology of dyskinesia, seizures, epilepsy, and ataxia [79]. Following we briefly discuss the role of ion channel modification in the most common neurodegenerative disorders age-related.

4.1 Ion channels and Alzheimer’s disease

AD is a kind of dementia marked by cognitive impairment, memory loss, and neuronal death. A buildup of Aβ peptides, tau hyperphosphorylation, and mutations in the catalytic domain of γ secretase are all elements that contribute to the disease’s focused characteristic. The ionic imbalance has been linked to AD development, and in particular an aberrant intracellular concentration of Ca²⁺, Na⁺, K⁺, and Cl⁻ [80]. Hardy and Higgins were the first to show that Aβ peptides disrupt Ca²⁺ homeostasis in neurons and increase intracellular Ca²⁺, which Mattson and his colleagues later validated [81]. Currently, multiple investigations have established the base for a novel concept: Aβ peptide is dangerous to neurons in part because it forms abnormal ion channels in neuronal membranes, disrupting neuronal homeostasis [82, 83, 84, 85, 86, 87]. Normally, an influx of Ca²⁺ ions is strictly controlled, evoking the release of neurotransmitters like glutamate from presynaptic terminals and triggering downstream signals that regulate cellular processes including synaptogenesis, synaptic transmission, synaptic plasticity, neuronal development, and survival. However, in AD, Ca²⁺ flux is disrupted as a result of increased oxidative stress and disrupted energy metabolism, which affects the glutamate receptor, glucose transporters, and ion-motive ATPases’ normal function [88]. In the hippocampus and cortex region in the brain, for instance, accumulated Aβ has been found to elevate the cellular Ca²⁺ ion level by plasma membrane L-type Ca²⁺ channels and Na⁺/K⁺- ATPase activity causing extreme excitatory responses, i.e., glutamate excitotoxicity and neuronal mortality [89]. Presenilin-1, the catalytic subunit of γ secretase, is also identified to be responsible for leaking Ca²⁺ ions from the endoplasmic reticulum to the cytoplasm via Ca²⁺ leak channels, increasing the cellular burden of Ca²⁺ ion in the AD brain [90]. Additionally, new research has revealed that transient receptor potential (TRP) channels impair Ca²⁺ homeostasis in Alzheimer’s disease. Thus, elevated intracellular Ca²⁺ ion alters amyloid-β precursor protein (AβPP) processing and influences various downstream pathways, including tau metabolism, housekeeping gene suppression, and autophagic function loss, worsening the symptoms of AD [91]. K⁺ channel abnormalities have also been identified in AD patients. Because the K⁺ channel is essential for the formation of action potentials and the maintenance of the resting potential, any blockage causes poor neurotransmission and neuronal injury. Furthermore, accumulating Aβ has been found in hippocampus neurons to suppress voltage-dependent fast-inactivating K⁺ currents [92]. Moreover, Kv1.3, Kv1.5, KCNN4/KCa3.1 respectively voltage-gated K⁺ channels and calcium-activated K⁺ channel, have been reported to induce neurodegeneration in response to neuroinflammation caused by Aβ peptides via microglial activation [93]. Similarly, the Kv3 subfamilies of K⁺ channel subunits, which can rapidly repolarize the action potential, have been reported to be impaired and downregulated in AD [94]. As a result of the increased K⁺ channel activity, intracellular Ca²⁺ overload occurs, leading to altered neuronal excitability and perhaps neuronal death [95]. On the plasma membrane of activated microglial cells in the hippocampus of mild AD patients, a novel intracellular chloride channel 1 (CLIC1) was recently discovered. CLIC1 channels become strongly expressed after Aβ stimulation of microglia and are responsible for the change in membrane anion permeability of the cell, resulting in neuronal death [96]. In addition to these channels, nAChR also plays a key role in the AD brain because cholinergic depletion may raise the production of Aβ and exacerbate its neurotoxicity through an alteration of the signal transduction events combined with cholinergic neurotransmission [97]. Additionally, the expressions of nAChR subtypes, are described to be highly expressed in AD-affected brain regions, thereby suggesting a role of these receptors in the AD etiopathology [98]. Tan and colleagues reviewed different calcium channel blockers dihydropyridines, benzothiazepines, and phenylalkylamines [99]. Moreover, Wiseman and Jarvik also reviewed different patents on potassium channel blockers or activators as possible therapies against AD such as 2-(phenylamino) benzimidazole, 2-amino benzimidazole derivatives, bis-benzimidazoles & related compounds, and many others [100]. Last but not least, as possible sodium channel blockers with useful property against AD, Shaikh and colleagues propose Aptiom (eslicarbazepine acetate) [101]. Unfortunately, we are still a long way from real AD therapy.

4.2 Ion channels and Parkinson’s disease

After AD, PD is the most prevalent brain disease, affecting 1% of the elderly population (60–65 years). It is characterized by bradykinesia, postural instability stiffness, and resting tremor. PD pathogenesis is caused by a number of variables, including activities linked to cellular Ca²⁺ excess, mitochondrial malfunction, oxidative or metabolic stress, and, in particular, a small number of neurotoxins that render neuronal cells more susceptible to cell death [102]. For example, the ATP-sensitive potassium channel Kir6.2, which induces excitotoxicity, is abundantly expressed in dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and has been linked to disease development [103]. Similarly, mutations in the Kir3.2 channel render it nonselective, producing an increase in the conduction of Na⁺ ions as a replacement for highly selective K⁺ ions, resulting in the loss of cerebellar cells and DA neurons in the SNc [55]. An important study by Sheih and colleagues also demonstrate that Kir3.1 and Kir3.2 are involved in the direct degeneration of DA neurons in the PD brain. Similarly, also voltage-gated T-type Ca²⁺ channels (TTCCs), Ca²⁺−sensitive voltage-gated A-type K⁺ channels, voltage-gated LTCCs (L-type Ca²⁺ channels), and ATP-sensitive K⁺ (K-ATP) channels contribute toward basal ganglia dysfunction in SNc DA neurons thereby leading to progressive loss of neuronal firing, thus causing PD [55]. In addition to a subset of medial SNc DA neurons, K-ATP channel activation aided the transition from tonic firing to NMDAR-mediated bursting in vivo, resulting in phasic DA release. When glutamate binds to the receptor, it causes the NMDAR channel to open, allowing Ca²⁺ to flow into the cell. As a result, any changes in glutamate transmission generate dyskinesias in people with PD [104]. Recently, it was discovered that a new ion channel, the Hv1 proton channel, is expressed in human brain microglia and immune tissues and that it is required for NADPH oxidase superoxide generation during the respiratory burst in phagocytic leukocytes, which can lead to neurodegeneration such as PD [105]. Also, in this case, different studies proposed ion channel modulators against PD such as 4-amino-7-chloroquinoline, Safinamide, verapamil (phenylalkylamine), and diltiazem (benzothiazepine) [106, 107].

4.3 Ion channels and Huntington’s disease

HD is a hereditary neurodegenerative disorder characterized by cognitive loss, emotional imbalance, and uncoordinated movements. It is caused by an autosomal dominant mutation in the Huntingtin (Htt) gene responsible for the expansion of CAG trinucleotide repeat >36 that leads to the synthesis of polyglutamine tract, thus mutated HTT (mHTT) protein is prone to aggregation and found to form intracellular accumulations in different cell types [108]. Using mouse models, Tong et al. studied the functional implications of ion channels in several cell types to determine the etiopathology of HD. In mHTT-expressing striatal astrocytes, altered Kir4.1 channel activity impaired extracellular K⁺ homeostasis, resulting in hyperexcitability, i.e., HD motor symptoms in striatal neurons. However, the normal Kir4.1 channel is one of the most important astrocytal K⁺ channels, since it is required for cell resting membrane potential and extracellular K⁺ buffering in the brain [109]. Furthermore, mHTT has been shown to affect the function of high-voltage-activated (HVA) Ca²⁺ channels in HD [110]. Aside from Ca²⁺ channel malfunction, also Na⁺, K⁺, Cl⁻ ion channels have demonstrated lower expression in HD animal models in multiple studies [111]. In striatal neurons of HD transgenic mice models, other researchers discovered the reduced expression of K⁺ channel subunits. Furthermore, in the R6/2 HD mouse model, expression of the muscular ClC-1 chloride channel is significantly reduced; thus, functional alteration of these channels disrupts ion homeostasis in cortical pyramidal neurons, affecting neurotransmitter release, synaptic integration, and genetic expression, all of which contribute to cortical dysfunction in HD [112, 113]. For HD, different calcium channel modulator has been proposed, such as 6-amino-4-(4-phenoxyphenethyl-amino)quinazoline (EVP4593), Inositol 1,4,5-Trisphosphate (Ip₃-sponge), Brilliant Blue G, and others, but the way is still long [114, 115].

4.4 Ion channels in multiple sclerosis and amyotrophic lateral sclerosis

MS is an immune-mediated central nervous system degenerative condition characterized by progressive demyelination in patches throughout the brain and spinal cord. Loss of coordination, muscle weakness, visual, and lingual problems are common signs of this condition, which affects young people in industrialized cultures the most. The presence of macrophages, T lymphocytes, microglia, and dendritic cells has been associated with inflammatory neuronal injury [116]. Infiltrating lymphocytes and macrophages harm neurons largely by direct cell contact or toxicity mediators such as glutamate or nitric oxide, as well as indirectly through the loss of oligodendrocytes and myelin sheath. Apart from inflammatory mediators, redistribution of voltage/ligand-gated ion channels and transporters has been linked to intracellular calcium excess, mitochondrial dysfunction, changes in electrical activity, and neuronal death [117]. Further, alterations in the expression pattern of Nav1.2, Nav1.5, Nav1.6, and Nav1.8, specific voltage-gated Na⁺ channel isoforms have been reported in MS, and their overworking is involved in axonal deterioration followed by cerebellar dysfunction [118]. Furthermore, Nav channels cause a Na⁺ influx into axons, which raises the amount of intra-axonal Ca²⁺ ions and interferes with axon myelination, resulting in MS pathogenicity. Different calcium and potassium channel isoforms were also shown to be increased, interfering with conduction in demyelinating axons [119]. ALS is a fatal chronic motor neurodegenerative disease marked by significant motor neuron loss in the motor cortex, brain stem, and spinal cord. Patients develop progressive muscle weakening, fasciculation, and atrophy, which leads to a loss of voluntary movement [120]. However, the specific etiology of ALS remains unknown, however, animal models are being used in research to find a feasible reason. Previous research revealed that the contraction of mammalian denervated muscle fibers is caused by spontaneous activation of the voltage-gated Na⁺ channel [121]. Furthermore, in human sporadic ALS, a significant drop in potassium channel expression has been found [122]. Axonal hyperexcitability is caused by continuous Na⁺ ion conduction followed by a rapid reduction in K⁺ ion conductance, resulting in ALS symptoms [123]. Furthermore, in ALS, motor neurons that innervate tongue muscles are prone to degeneration, which has been related to VGCC expression differences. In ALS patients and animal models, other investigations have found immunoreactivity with several calcium ion channels [124]. Israelson et al. investigated the role of mitochondrial channelopathy during ALS and discovered that mutant superoxide dismutase 1 (SOD1) inhibits the mitochondrial voltage-dependent anion channel-1 and induces mitochondrial-dependent apoptosis, resulting in lethal paralysis in ALS. However, further study is being conducted to determine the specific mechanism responsible for its etiology [43, 125]. There is a lack of data to address the review question on the efficacy of Na⁺ channel blockers for people with MS [126]. The K⁺ channel blocker Fampridine-SR is an authorized MS therapy adjunct that has been demonstrated to help with ambulation, tiredness, and endurance [127]. Silva et al. demonstrated the efficacy of Ca²⁺ channel blocker CTK 01512-2 in mouse models of MS comparing it with Ziconotide. They found a significant improvement in neuroinflammatory event MS-related [128].

5. Conclusion

Ion channel dysfunction is steadily becoming connected to neurological disorders, making it an intriguing subject of neuroscience research. It has been linked to memory loss, movement issues, and neuromuscular anomalies in a number of neurological diseases. Since they originate in response to genetic defects in channel coding proteins that disturb the ionic equilibrium in the brain, the majority of these illnesses are classified as neurological channelopathies. Aging is a complex and multidimensional biological process that affects all organ systems. In the core section of them, cellular malfunction and senescent cell accumulation are common. Various aspects of brain aging have been discovered at the molecular, cellular, and tissue levels, according to research in the fields of aging and neurobiology. Aging is the leading risk factor for a broad range of neurodegenerative disorders. According to breakthroughs in the treatment and prevention of some tough diseases such as cardiovascular disease and malignancies, which have enabled more people to survive past the age of 70, aging brain disorders have lately become the leading cause of disability and death. After providing an overview of recent developments in brain aging, the current review describes it as the result of decreased neurogenesis and synaptic plasticity, as well as altered neurochemical and signaling pathways, such as impaired protein processing, glial cell activation, impaired mitochondrial function, increased oxidative stress, and neuroinflammation. Furthermore, the hippocampus and neocortex are the principal susceptible sections, with varying degrees of molecular and cellular abnormalities in their sub-centers as a result of aging. Although each of these age-related alterations is present during normal aging, their combined influence, when combined with genetic background and environmental variables, may trigger the cytotoxic activation cycle. Transcript factors, proteins, and cell-environmental variables including redox potential are all connected to these alterations. However, the crucial component that governs the entire activity is unclear. One of the first priorities would be to figure out how redox capability influences gene transcription and promotes metabolic responses as the brain matures. Our understanding of brain aging is still in its early stages. More research is needed to discover effective therapy approaches and drugs to combat brain aging. Furthermore, non-pharmacological techniques such as lifestyle adjustments, physical exercise, and calorie restriction, which promote the brain’s physiological processes while reducing ROS formation and inflammation, may help to promote healthy aging. Understanding the processes that underpin the hallmarks is crucial for developing future therapeutics to slow or even reverse the aging process in the brain. The primary objective of neurobiology and brain aging research should be to discover methods and techniques for supporting healthy brain aging in all people. The functional activities of ion channels connected to the onset of numerous chronic neurological diseases have been determined. NDDs are accompanied with inflammations, neurotoxic protein accumulations, physiological stress, and mitochondrial dysfunctions, according to experimental findings. These abnormal alterations cause disruptions in normal physiological processes and brain homeostasis, which leads to illness development. The pathogenesis of AD, PD, HD, MS, and ALS has been further clarified in terms of faulty ion channels. Until today many natural compounds or synthetics compounds are identified as a modulator of ion channels (for a very extensive review refer to [43, 129]). Furthermore, channel modulators have been discovered to be important in correcting the chronic consequences of abnormal ion channels. Furthermore, understanding their regulation mechanisms in neurodegeneration might lead to the development of newer, more effective treatment techniques.

Conflict of interest

The authors declare no conflict of interest.