Open access peer-reviewed chapter

Ion Channels and Neurodegenerative Disease Aging Related

Written By

Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola

Submitted: 19 January 2022 Reviewed: 07 February 2022 Published: 08 June 2022

DOI: 10.5772/intechopen.103074

From the Edited Volume

Ion Transporters - From Basic Properties to Medical Treatment

Edited by Zuzana Sevcikova Tomaskova

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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.


  • aging
  • ion channels
  • neurodegeneration
  • therapeutic targets

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.


  1. 1. Tosato M et al. The aging process and potential interventions to extend life expectancy. Clinical Interventions in Aging. 2007;2(3):401-412
  2. 2. Zia A et al. Molecular and cellular pathways contributing to brain aging. Behavioral and Brain Functions. 2021;17(1):6
  3. 3. Mariani E et al. Oxidative stress in brain aging, neurodegenerative and vascular diseases: An overview. Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences. 2005;827(1):65-75
  4. 4. Strickland M et al. Relationships between ion channels, mitochondrial functions and inflammation in human aging. Frontiers in Physiology. 2019;10:158
  5. 5. Patel R, Sesti F. Oxidation of ion channels in the aging nervous system. Brain Research. 2016;1639:174-185
  6. 6. Exercise for female cardiac patients? Several factors play a role in continued commitment. American Journal of Nursing. 2003;103(10):17-17
  7. 7. Floyd RA, Hensley K. Oxidative stress in brain aging. Implications for therapeutics of neurodegenerative diseases. Neurobiology of Aging. 2002;23(5):795-807
  8. 8. Huffman K. The developing, aging neocortex: How genetics and epigenetics influence early developmental patterning and age-related change. Frontiers in Genetics. 2012;3:212
  9. 9. Lemoine M. The evolution of the hallmarks of aging. Frontiers in Genetics. 2021;12:693071
  10. 10. Peng K et al. Mitochondrial ATP-sensitive potassium channel regulates mitochondrial dynamics to participate in neurodegeneration of Parkinson’s disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2018;1864(4 Pt A):1086-1103
  11. 11. Bokov A, Chaudhuri A, Richardson A. The role of oxidative damage and stress in aging. Mechanisms of Ageing and Development. 2004;125(10-11):811-826
  12. 12. Cini M, Moretti A. Studies on lipid peroxidation and protein oxidation in the aging brain. Neurobiology of Aging. 1995;16(1):53-57
  13. 13. Halliwell B. Role of free radicals in the neurodegenerative diseases: Therapeutic implications for antioxidant treatment. Drugs & Aging. 2001;18(9):685-716
  14. 14. Park L et al. Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. Journal of Cerebral Blood Flow and Metabolism. 2007;27(12):1908-1918
  15. 15. Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nature Reviews. Drug Discovery. 2013;12(12):931-947
  16. 16. Calabrese V et al. Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: Evidence for a protective role of acetylcarnitine. Neurochemical Research. 2003;28(9):1321-1328
  17. 17. Delves PJ, Roitt IM. The immune system. Second of two parts. The New England Journal of Medicine. 2000;343(2):108-117
  18. 18. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. The Journal of Pathology. 2007;211(2):144-156
  19. 19. Franceschi C et al. An evolutionary perspective on immunosenescence. Annals of the New York Academy of Sciences. 2000;908:244-254
  20. 20. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cellular Signalling. 2012;24(4):835-845
  21. 21. Yaffe K et al. Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology. 2003;61(1):76-80
  22. 22. Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochemical Pharmacology. 2014;88(4):594-604
  23. 23. von Bernhardi R, Eugenin-von Bernhardi L, Eugenin J. Microglial cell dysregulation in brain aging and neurodegeneration. Frontiers in Aging Neuroscience. 2015;7:124
  24. 24. Kim SU, de Vellis J. Microglia in health and disease. Journal of Neuroscience Research. 2005;81(3):302-313
  25. 25. Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: Uncovering the molecular mechanisms. Nature Reviews. Neuroscience. 2007;8(1):57-69
  26. 26. Liu X et al. Age-dependent neuroinflammatory responses and deficits in long-term potentiation in the hippocampus during systemic inflammation. Neuroscience. 2012;216:133-142
  27. 27. Raj DD et al. Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiology of Aging. 2014;35(9):2147-2160
  28. 28. Snow WM et al. Roles for NF-kappaB and gene targets of NF-kappaB in synaptic plasticity, memory, and navigation. Molecular Neurobiology. 2014;49(2):757-770
  29. 29. Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. The EMBO Journal. 2017;36(11):1474-1492
  30. 30. Rose CR et al. Astroglial glutamate signaling and uptake in the Hippocampus. Frontiers in Molecular Neuroscience. 2017;10:451
  31. 31. Barger SW et al. Tumor necrosis factors alpha and beta protect neurons against amyloid beta-peptide toxicity: Evidence for involvement of a kappa B-binding factor and attenuation of peroxide and Ca2+ accumulation. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(20):9328-9332
  32. 32. Kassed CA et al. Mice expressing human mutant presenilin-1 exhibit decreased activation of NF-kappaB p50 in hippocampal neurons after injury. Brain Research. Molecular Brain Research. 2003;110(1):152-157
  33. 33. Kassed CA et al. Lack of NF-kappaB p50 exacerbates degeneration of hippocampal neurons after chemical exposure and impairs learning. Experimental Neurology. 2002;176(2):277-288
  34. 34. Pennypacker KR et al. NF-kappaB p50 is increased in neurons surviving hippocampal injury. Experimental Neurology. 2001;172(2):307-319
  35. 35. Bruccoleri A, Pennypacker KR, Harry GJ. Effect of dexamethasone on elevated cytokine mRNA levels in chemical-induced hippocampal injury. Journal of Neuroscience Research. 1999;57(6):916-926
  36. 36. Pennypacker K, Fischer I, Levitt P. Early in vitro genesis and differentiation of axons and dendrites by hippocampal neurons analyzed quantitatively with neurofilament-H and microtubule-associated protein 2 antibodies. Experimental Neurology. 1991;111(1):25-35
  37. 37. Wang X et al. Cytosolic prion protein induces apoptosis in human neuronal cell SH-SY5Y via mitochondrial disruption pathway. BMB Reports. 2009;42(7):444-449
  38. 38. Bryant L et al. Spinal ceramide and neuronal apoptosis in morphine antinociceptive tolerance. Neuroscience Letters. 2009;463(1):49-53
  39. 39. Gao HL et al. Zinc deficiency reduces neurogenesis accompanied by neuronal apoptosis through caspase-dependent and -independent signaling pathways. Neurotoxicity Research. 2009;16(4):416-425
  40. 40. Wu JS et al. Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation. 2009;119(8):1124-1134
  41. 41. Li J et al. Protection of PMS777, a new AChE inhibitor with PAF antagonism, against amyloid-beta-induced neuronal apoptosis and neuroinflammation. Cellular and Molecular Neurobiology. 2009;29(4):589-595
  42. 42. Chen L et al. Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. The International Journal of Biochemistry & Cell Biology. 2009;41(6):1284-1295
  43. 43. Kumar P et al. Ion channels in neurological disorders. Advances in Protein Chemistry and Structural Biology. 2016;103:97-136
  44. 44. Cooper EC, Jan LY. Ion channel genes and human neurological disease: Recent progress, prospects, and challenges. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(9):4759-4766
  45. 45. Lodish H et al. Molecular Cell Biology. New York City, United States: Macmillan; 2008
  46. 46. Barnett MW, Larkman PM. The action potential. Practical Neurology. 2007;7(3):192-197
  47. 47. Strange K. Cellular volume homeostasis. Advances in Physiology Education. 2004;28(1-4):155-159
  48. 48. Hoppa MB et al. Control and plasticity of the presynaptic action potential waveform at small CNS nerve terminals. Neuron. 2014;84(4):778-789
  49. 49. Rowan MJ et al. Synapse-level determination of action potential duration by K(+) channel clustering in axons. Neuron. 2016;91(2):370-383
  50. 50. Charpentier M et al. Nuclear-localized cyclic nucleotide-gated channels mediate symbiotic calcium oscillations. Science. 2016;352(6289):1102-1105
  51. 51. Raffaello A et al. Calcium at the center of cell signaling: Interplay between endoplasmic reticulum, mitochondria, and lysosomes. Trends in Biochemical Sciences. 2016;41(12):1035-1049
  52. 52. Kurachi Y, North A. Ion channels: Their structure, function and control–an overview. The Journal of Physiology. 2004;554(2):245-247
  53. 53. Santulli G, Marks AR. Essential roles of intracellular calcium release channels in muscle, brain, metabolism, and aging. Current Molecular Pharmacology. 2015;8(2):206-222
  54. 54. Rao V, Kaja S, Gentile S. Ion Channels in Aging and Aging-Related Diseases. In: Shiomi N, editor. Molecular Mechanisms of the Aging Process and Rejuvenation [Internet]. London: IntechOpen; 2016 [cited 2022 Mar 23]. Available from: DOI: 10.5772/63951
  55. 55. Shieh CC et al. Potassium channels: Molecular defects, diseases, and therapeutic opportunities. Pharmacological Reviews. 2000;52(4):557-594
  56. 56. Tian C et al. Potassium channels: Structures, diseases, and modulators. Chemical Biology & Drug Design. 2014;83(1):1-26
  57. 57. Colom LV et al. Role of potassium channels in amyloid-induced cell death. Journal of Neurochemistry. 1998;70(5):1925-1934
  58. 58. Annunziato L et al. Modulation of ion channels by reactive oxygen and nitrogen species: A pathophysiological role in brain aging? Neurobiology of Aging. 2002;23(5):819-834
  59. 59. Yu SP, Canzoniero LM, Choi DW. Ion homeostasis and apoptosis. Current Opinion in Cell Biology. 2001;13(4):405-411
  60. 60. Yu SP et al. Role of the outward delayed rectifier K+ current in ceramide-induced caspase activation and apoptosis in cultured cortical neurons. Journal of Neurochemistry. 1999;73(3):933-941
  61. 61. Neher E, Sakaba T. Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron. 2008;59(6):861-872
  62. 62. Nikoletopoulou V, Tavernarakis N. Calcium homeostasis in aging neurons. Frontiers in Genetics. 2012;3:200
  63. 63. Toescu EC. Altered calcium homeostasis in old neurons. In: Riddle DR, editor. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): Taylor & Francis Group; 2007
  64. 64. Griffith WH et al. Modification of ion channels and calcium homeostasis of basal forebrain neurons during aging. Behavioural Brain Research. 2000;115(2):219-233
  65. 65. Gibson GE, Peterson C. Calcium and the aging nervous system. Neurobiology of Aging. 1987;8(4):329-343
  66. 66. Disterhoft JF, Moyer JR Jr, Thompson LT. The calcium rationale in aging and Alzheimer’s disease. Evidence from an animal model of normal aging. Annals of the New York Academy of Sciences. 1994;747:382-406
  67. 67. Khachaturian ZS. Calcium, membranes, aging, and Alzheimer’s disease. Introduction and overview. Annals of the New York Academy of Sciences. 1989;568:1-4
  68. 68. Gant JC et al. Aging-related calcium dysregulation in rat entorhinal neurons homologous with the human entorhinal neurons in which Alzheimer’s disease neurofibrillary tangles first appear. Journal of Alzheimer’s Disease. 2018;66(4):1371-1378
  69. 69. Michaelis ML et al. Decreased plasma membrane calcium transport activity in aging brain. Life Sciences. 1996;59(5-6):405-412
  70. 70. Thibault O, Gant JC, Landfield PW. Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: Minding the store. Aging Cell. 2007;6(3):307-317
  71. 71. Malenka RC et al. The impact of postsynaptic calcium on synaptic transmission—Its role in long-term potentiation. Trends in Neurosciences. 1989;12(11):444-450
  72. 72. Bliss TV, Collingridge GL. A synaptic model of memory: Long-term potentiation in the hippocampus. Nature. 1993;361(6407):31-39
  73. 73. Celsi F et al. Mitochondria, calcium and cell death: A deadly triad in neurodegeneration. Biochimica et Biophysica Acta. 2009;1787(5):335-344
  74. 74. Catterall WA. From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron. 2000;26(1):13-25
  75. 75. Catterall WA. Voltage-gated sodium channels at 60: Structure, function and pathophysiology. The Journal of Physiology. 2012;590(11):2577-2589
  76. 76. Caring for a dog with osteoarthritis. The Veterinary Record. 2018;182(15):440
  77. 77. Desaphy JF et al. Modification by ageing of the tetrodotoxin-sensitive sodium channels in rat skeletal muscle fibres. Biochimica et Biophysica Acta. 1998;1373(1):37-46
  78. 78. Veal EA, Day AM, Morgan BA. Hydrogen peroxide sensing and signaling. Molecular Cell. 2007;26(1):1-14
  79. 79. Simms BA, Zamponi GW. Neuronal voltage-gated calcium channels: Structure, function, and dysfunction. Neuron. 2014;82(1):24-45
  80. 80. Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxidative Medicine and Cellular Longevity. 2013;2013:316523
  81. 81. Hardy J. Alzheimer’s disease: The amyloid cascade hypothesis: An update and reappraisal. Journal of Alzheimer’s Disease. 2006;9(3 Suppl):151-153
  82. 82. Neelands TR, King AP, Macdonald RL. Functional expression of L-, N-, P/Q-, and R-type calcium channels in the human NT2-N cell line. Journal of Neurophysiology. 2000;84(6):2933-2944
  83. 83. Nimmrich V, Eckert A. Calcium channel blockers and dementia. British Journal of Pharmacology. 2013;169(6):1203-1210
  84. 84. Kim S, Rhim H. Effects of amyloid-beta peptides on voltage-gated L-type Ca(V)1.2 and Ca(V)1.3 Ca(2+) channels. Molecules and Cells. 2011;32(3):289-294
  85. 85. Danysz W, Parsons CG. Alzheimer’ disease, beta-amyloid, glutamate, NMDA receptors and memantine—Searching for the connections. British Journal of Pharmacology. 2012;167(2):324-352
  86. 86. Oules B et al. Ryanodine receptor blockade reduces amyloid-beta load and memory impairments in Tg2576 mouse model of Alzheimer disease. The Journal of Neuroscience. 2012;32(34):11820-11834
  87. 87. Parri RH, Dineley TK. Nicotinic acetylcholine receptor interaction with beta-amyloid: Molecular, cellular, and physiological consequences. Current Alzheimer Research. 2010;7(1):27-39
  88. 88. Itkin A et al. Calcium ions promote formation of amyloid beta-peptide (1-40) oligomers causally implicated in neuronal toxicity of Alzheimer’s disease. PLoS One. 2011;6(3):e18250
  89. 89. Camandola S, Mattson MP. Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochimica et Biophysica Acta. 2011;1813(5):965-973
  90. 90. Tu H et al. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer’s disease-linked mutations. Cell. 2006;126(5):981-993
  91. 91. Yamamoto S et al. Transient receptor potential channels in Alzheimer’s disease. Biochimica et Biophysica Acta. 2007;1772(8):958-967
  92. 92. Poulopoulou C et al. Aberrant modulation of a delayed rectifier potassium channel by glutamate in Alzheimer’s disease. Neurobiology of Disease. 2010;37(2):339-348
  93. 93. Kaushal V et al. The Ca2+−activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. The Journal of Neuroscience. 2007;27(1):234-244
  94. 94. Bhullar KS, Rupasinghe HP. Polyphenols: Multipotent therapeutic agents in neurodegenerative diseases. Oxidative Medicine and Cellular Longevity. 2013;2013:891748
  95. 95. Mocali A et al. Altered proteolysis in fibroblasts of Alzheimer patients with predictive implications for subjects at risk of disease. International Journal of Alzheimer’s Disease. 2014;2014:520152
  96. 96. Novarino G et al. Involvement of the intracellular ion channel CLIC1 in microglia-mediated beta-amyloid-induced neurotoxicity. The Journal of Neuroscience. 2004;24(23):5322-5330
  97. 97. Buckingham SD et al. Nicotinic acetylcholine receptor signalling: Roles in Alzheimer’s disease and amyloid neuroprotection. Pharmacological Reviews. 2009;61(1):39-61
  98. 98. Nery AA et al. Rescue of amyloid-Beta-induced inhibition of nicotinic acetylcholine receptors by a peptide homologous to the nicotine binding domain of the alpha 7 subtype. PLoS One. 2013;8(7):e67194
  99. 99. Tan Y, Deng Y, Qing H. Calcium channel blockers and Alzheimer’s disease. Neural Regeneration Research. 2012;7(2):137-140
  100. 100. Judge SI et al. Potassium channel blockers and openers as CNS neurologic therapeutic agents. Recent Patents on CNS Drug Discovery. 2007;2(3):200-228
  101. 101. Shaikh S et al. Aptiom (eslicarbazepine acetate) as a dual inhibitor of beta-secretase and voltage-gated sodium channel: Advancement in Alzheimer’s disease-epilepsy linkage via an enzoinformatics study. CNS & Neurological Disorders Drug Targets. 2014;13(7):1258-1262
  102. 102. Massano J, Bhatia KP. Clinical approach to Parkinson’s disease: Features, diagnosis, and principles of management. Cold Spring Harbor Perspectives in Medicine. 2012;2(6):a008870
  103. 103. Gong XG et al. Da-bu-yin-wan and qian-zheng-san to neuroprotect the mouse model of Parkinson’s disease. Evidence-based Complementary and Alternative Medicine. 2014;2014:729195
  104. 104. Schiemann J et al. K-ATP channels in dopamine substantia nigra neurons control bursting and novelty-induced exploration. Nature Neuroscience. 2012;15(9):1272-1280
  105. 105. Wu LJ et al. The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke. Nature Neuroscience. 2012;15(4):565-573
  106. 106. Kim CH, Leblanc P, Kim KS. 4-amino-7-chloroquinoline derivatives for treating Parkinson’s disease: Implications for drug discovery. Expert Opinion on Drug Discovery. 2016;11(4):337-341
  107. 107. Ritz B et al. L-type calcium channel blockers and Parkinson disease in Denmark. Annals of Neurology. 2010;67(5):600-606
  108. 108. Labbadia J, Morimoto RI. Huntington’s disease: Underlying molecular mechanisms and emerging concepts. Trends in Biochemical Sciences. 2013;38(8):378-385
  109. 109. Tong X et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington’s disease model mice. Nature Neuroscience. 2014;17(5):694-703
  110. 110. Miller BR, Bezprozvanny I. Corticostriatal circuit dysfunction in Huntington’s disease: Intersection of glutamate, dopamine and calcium. Future Neurology. 2010;5(5):735-756
  111. 111. Oyama F et al. Sodium channel beta4 subunit: Down-regulation and possible involvement in neuritic degeneration in Huntington’s disease transgenic mice. Journal of Neurochemistry. 2006;98(2):518-529
  112. 112. Ariano MA et al. Striatal potassium channel dysfunction in Huntington’s disease transgenic mice. Journal of Neurophysiology. 2005;93(5):2565-2574
  113. 113. Waters CW et al. Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(22):9160-9165
  114. 114. Czeredys M. Dysregulation of neuronal calcium signaling via store-operated channels in Huntington’s disease. Frontiers in Cell and Development Biology. 2020;8:611735
  115. 115. Jo S, Bean BP. Inhibition of neuronal voltage-gated sodium channels by brilliant blue G. Molecular Pharmacology. 2011;80(2):247-257
  116. 116. Fitzner D, Simons M. Chronic progressive multiple sclerosis—Pathogenesis of neurodegeneration and therapeutic strategies. Current Neuropharmacology. 2010;8(3):305-315
  117. 117. Meuth SG et al. Multiple sclerosis—A channelopathy? Targeting ion channels and transporters in inflammatory neurodegeneration. Nervenarzt. 2009;80(4):422-429
  118. 118. Waxman SG. Axonal conduction and injury in multiple sclerosis: The role of sodium channels. Nature Reviews. Neuroscience. 2006;7(12):932-941
  119. 119. Judge SI et al. Voltage-gated potassium channels in multiple sclerosis: Overview and new implications for treatment of central nervous system inflammation and degeneration. Journal of Rehabilitation Research and Development. 2006;43(1):111-122
  120. 120. Guatteo E et al. Altered calcium homeostasis in motor neurons following AMPA receptor but not voltage-dependent calcium channels’ activation in a genetic model of amyotrophic lateral sclerosis. Neurobiology of Disease. 2007;28(1):90-100
  121. 121. Pietrobon D. Calcium channels and channelopathies of the central nervous system. Molecular Neurobiology. 2002;25(1):31-50
  122. 122. Shibuya K et al. Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: An immunohistochemical study. Experimental Neurology. 2011;232(2):149-153
  123. 123. Kanai K et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: Impaired potassium channel function related to disease stage. Brain. 2006;129(Pt 4):953-962
  124. 124. Gonzalez LE et al. Amyotrophic lateral sclerosis-immunoglobulins selectively interact with neuromuscular junctions expressing P/Q-type calcium channels. Journal of Neurochemistry. 2011;119(4):826-838
  125. 125. Israelson A et al. Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS. Neuron. 2010;67(4):575-587
  126. 126. Yang C et al. Sodium channel blockers for neuroprotection in multiple sclerosis. Cochrane Database of Systematic Reviews. 2015;10:CD010422
  127. 127. Morrow SA, Rosehart H, Johnson AM. The effect of Fampridine-SR on cognitive fatigue in a randomized double-blind crossover trial in patients with MS. Multiple Sclerosis and Related Disorders. 2017;11:4-9
  128. 128. Silva RBM et al. Beneficial effects of the Calcium Channel blocker CTK 01512-2 in a mouse model of multiple sclerosis. Molecular Neurobiology. 2018;55(12):9307-9327
  129. 129. Alexander SP et al. The concise guide to pharmacology 2021/22: Ion channels. British Journal of Pharmacology. 2021;178:S157-S245

Written By

Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola

Submitted: 19 January 2022 Reviewed: 07 February 2022 Published: 08 June 2022