Reduction of neuronal hyperexcitability with modulation of T-type calcium channel or SK channel in essential tremor

Abstract

Essential tremor is one of the most prevalent movement disorders. Propranolol and primidone are the first-line pharmacological therapies with symptomatic control in less than 50% of patients. The next line of treatment includes topiramate, alprazolam, clonazepam, gabapentin, and botulinum toxin injections. These medications that lead to modest improvements are commonly used as add-on agents. Surgical therapies, including deep brain stimulation (DBS) surgery and focused ultrasound beam, targeted to the thalamus, are considered for treating tremor refractory to medications and have been found to lead to greater than 75% improvement in tremor symptoms. However, DBS is a costly invasive procedure; some patients report tolerance to benefits, and focused ultrasound therapy leading to brain lesions is associated with a possibility for permanent clinical deficits. Therefore, research efforts to develop the next generation of oral medications with greater benefits and lesser adverse effects are warranted. There is considerable evidence that the increased functions of calcium channels (P/Q-type and T-type channels) and reduced functions of calcium-activated potassium channels (SK channels) located in the neuronal membranes lead to tremor oscillations. Consequently, many new pharmacological studies are targeting these channels to leverage better clinical outcomes. The current review will discuss the pathophysiology, the specific importance of these channels, and the early clinical experience of using compounds targeting these channels to treat essential tremor.

Introduction

Essential tremor is one of the most prevalent movement disorder in the world, affecting about 4% of the population after the age of 40 years.^{1 2 3 4} The oscillatory movements in the hands presenting during everyday motor tasks can be functionally disabling and socially embarrassing.⁵ The currently available treatments for essential tremor are mainly symptomatic, with propranolol and primidone as the first-line drugs. Clinical evidence indicates that only 50% of patients benefit from one or both of these medications. Propranolol, a beta-blocker approved by the FDA, blocks the beta-2 receptors found in the peripheral muscle spindles that send feedback signals to the brain; however, aside from peripheral actions, the medication also directly affects the central brain circuitries.^{6 7} Primidone on the other hand has pure central actions. The main compound regulates the sodium and calcium channels in the neuronal membrane, whereas phenobarbital, a metabolite acts on the inhibitory GABA-A receptors.⁸ The next line of treatment includes topiramate, alprazolam, clonazepam, gabapentin and botulinum toxin injections.⁹ These medications commonly used as add-on agents reveal a lower degree of improvements in the range of 30–40%.¹⁰ Surgical therapies, including deep brain stimulation (DBS) surgery^{11 12} and focused ultrasound beam targeted to the thalamus, are considered when the tremor persists despite multiple medication trials or when there are intolerable adverse effects.¹³ While the surgical therapies are no doubt powerful, they have limitations. For example, DBS surgery is invasive and costly, and in the long term, some patients have diminished clinical response due to tolerance to stimulation effects. Then, focused ultrasound therapy leads to creation of brain lesions, potentially resulting in permanent clinical deficits. Thus, the next generation of oral medications with greater benefits and lesser adverse effects is highly warranted.

In the last decade, there has been a significant advancement in the neuronal and network-level understanding of the pathophysiology of essential tremor. In addition to the P/Q-type calcium channels, T-type calcium channels and calcium-activated potassium channels (SK channels) present in the neuronal membranes are increasingly recognized to generate tremor oscillations within the brain network. There are ongoing efforts to develop pharmacological compounds targeting these channels to gain better clinical outcomes. The current review will discuss the pathophysiology, the role of the P/Q-type calcium channel, and the evolving experience with novel compounds targeting specific subtypes of T-type calcium channels and SK channels for treating essential tremor.

Pathophysiology of Essential Tremor:

Network model theory

Many studies have shown that an oscillatory dysfunction involving the olivo-cerebello-thalamo-cortical network is the pathophysiological hallmark for essential tremor.^{14 15 16 17 18} The electrical properties of neurons in the olivary and cerebellar nuclei and the thalamus that relay to the motor cortex have unique oscillatory properties. Membrane hyperpolarization causes rebound change in membrane potentially leading to oscillatory firing of the neurons at a given frequency.^{19 20} Cellular bursts in the cerebellar receiving zone of the thalamus (ventral intermediate nucleus or Vim) have been found to correlate strongly with the peripheral tremor signal.²¹ Magnetoencephalography and electroencephalography studies, have also shown a significant coherence between the contralateral motor cortex, thalamus and ipsilateral cerebellum and the peripheral tremor signal.²² The inferior olivary nucleus, cerebellum, Vim and motor cortex together form the network leading to generation of tremor oscillations.

Are there single or multiple oscillators?

Membrane hyperpolarization of pathogenic neurons leads to independent oscillatory behavior at a given frequency.^{19 20} While this theory is well accepted, it is still not clear whether a single oscillator or multiple sources of oscillations are involved in the pathophysiology. Microelectrode recordings from the thalamus during the DBS surgery have shown presence of multiple spatially separated clusters of tremor cells.²³ A recent study found that essential tremor demonstrates a low tolerance for frequency change which means that the oscillating system does not have the capability of maintaining several resonant frequencies. The multiple pathogenic oscillators within the tremor network generate a more finely tuned convergent drive to the peripheral muscles.^{24 25} Although the coherence between the motor cortex neurons and peripheral tremor activity could be intermittent,^{26 27} the multiple oscillators are observed to couple during the performance of the motor tasks.

Origins of tremor oscillations: an inferior olivary nucleus or the cerebellum?

There is consensual agreement that the olivo-cerebello-thalamo-cortical network is dysfunctional in essential tremor; however, the exact origins of the oscillatory signals remain to be confirmed.¹⁶ Previously, the proximal elements of the network, such as the inferior olivary nucleus and the cerebellar cortex, were supposedly the main potential pacemakers. Depolarization of the inferior olivary neurons that depends on the high-threshold and low-threshold calcium and potassium currents led to generation of tremor oscillations.²⁸ In early animal models of tremor, exposure to harmaline, a plant alkaloid resulted in hyperpolarization of the inferior olivary neurons.^{29 30} The hyperpolarization led to the generation of 4– to 10– Hz burst oscillations in the olivocerebellar pathways or the climbing fibers.^{31, 32} These oscillations were then transmitted to the cerebellar cortex, eventually manifesting behaviorally as an action tremor.^{33 34}

Recently concerns were raised whether the inferior olivary neurons played any pacemaker role as most evidence to date is from animal models with no concordant evidence in humans.³⁵ For example, imaging studies in patients with essential tremor found clear abnormalities in the cerebellum, thalamus and the motor cortex but structural or functional abnormalities affecting the inferior olivary nucleus could not be confirmed.³⁶ Archer et al found that visual feedback increased tremor amplitude and the tremor-related activity in the cerebello-thalamo-cortical network.³⁷ These abnormalities extended to the supplementary motor area, visual and parietal areas, but the inferior olive did not reveal any change. Furthermore, a post-mortem study found that the pathological examination of the inferior olivary nucleus in essential tremor patients was not significantly different from the healthy controls.^{38 39} Therefore, the role of the olivary nucleus in the context of essential tremor pathogenesis has become increasingly questionable.

On the other hand, several lines of evidence indicate that the cerebellum is the primary pathophysiological substrate for essential tremor. Quantitative gait and limb movement assessment has revealed coordination abnormalities similar to ataxia in patients with essential tremor.^{40 41} While magnetic resonance spectroscopy has revealed decreased levels of N-acetyl aspartate in the cerebellum, a finding that indicates loss or dysfunction of neurons,⁴² PET studies have shown increased cerebellar metabolism in essential tremor patients.^{43 44} Pathological studies have shown axonal swellings in the Purkinje cells, swellings in and regression of the Purkinje cell dendritic arbor and Purkinje cell death.^{45 46, 47 48 49} Some investigators advocate that the cerebellum decouples or disconnects from the thalamus and the motor cortex (cerebellar decoupling hypothesis), leading to pathological oscillations.⁵⁰ In a functional MRI study, a significantly decreased connectivity between the dentate nucleus and cortical and subcortical brain regions was seen, indicating a functional disconnection of the dentate nucleus from the rest of the network.⁵¹ In other structural MRI studies, white matter integrity of the cerebellar peduncles in patients with clinical tremor was reduced providing further support that the cerebellum is disconnected or decoupled from the rest of the network.^{52 53} In contrast to the decoupling hypothesis, the oscillator hypothesis proposes the cerebellum as the primary driving oscillator. In an fMRI study, patients were examined in the scanner with DBS turned on and off and with arms examined at rest and postural elevation.⁵⁴ DBS therapy led to normalization of cerebellar activity within the sensorimotor cerebellar lobules (IV/V and VIII) supporting a cerebellar oscillator or cerebellar hyperexcitability hypothesis^{55 14}

Purkinje cell neurons in the cerebellar cortex: hyperexcitability hypothesis

Purkinje cells are large neurons in the cerebellar cortex that characteristically have an elaborate fan-shaped dendritic arbor with a large number of spines. Dendritic spines receive glutamatergic excitatory fibers from two sources; the climbing and the parallel fibers.⁵⁶ The climbing fibers originate from the inferior olivary nucleus and they form excitatory synapses with dendritic spines that are located proximal to the Purkinje cell soma. Parallel fibers originate from the granule cells in the cerebellar cortex; they pass orthogonally through the dendritic arbor to form a granule-cell-Purkinje-cell synapse. In contrast to the parallel and climbing fibers, basket and stellate cells (found in the cerebellar molecular layer) provide inhibitory (GABAergic) input to the Purkinje cell.⁵⁷

At birth, multiple climbing fibers innervate the Purkinje cells. However, the maturation of microcircuitries during the early postnatal period leads to eliminating surplus climbing fibers, also known as “pruning.”⁵⁸ The remaining single climbing fiber ends up providing strong excitatory input to the Purkinje cell neuron whereas the parallel fibers that are as many as 100,000 in number provide weak excitatory input.⁵⁹ In patients with essential tremor, pruning of climbing fiber - Purkinje cell synapses is reportedly deficient⁶⁰ whereas the density, counts and integrity of parallel fiber remain intact when comparing to healthy control brains.⁶¹ In a mouse model study involving optogenetic manipulation, excessive activity at the climbing fiber - Purkinje cell synapse was found to correlate with excessive oscillatory activity.⁶² These mouse model findings were confirmed by another group of investigators who found patterned firings of Purkinje cell neurons were generated in response to optogenetics and these led to powerful oscillatory signals.⁴⁷ Thus, growing and compelling evidence points to abnormal Purkinje cell firing as a critical neural substrate for essential tremor.⁶³ Whether these neurons generate oscillatory signals or they propagate existing tremor signals needs further examination as some studies have found abnormalities in cells directly upstream⁶⁴ as well as in the cerebellar nuclei directly downstream.⁶⁵

Purkinje cells generate simple spikes and complex spikes (highly stereotyped burst of decrementing spikes) to communicate with the downstream output neurons of the cerebellar nuclei.^{66 56} Simple spikes are high frequency 50 Hz spikes driven by intrinsic ion channels expressed by the Purkinje cells whereas complex spikes are driven by large voltage-gated calcium channels in the dendrites of neurons that respond to excitatory input from the climbing fiber.⁶⁷ (Figure 1) Another striking feature of Purkinje cell is the tendency to fire in bursts. Bursts consists of 3–20 spikes with a stereotypical waveform. The rate and pattern of firing of Purkinje cells are controlled both by synaptic input and by intrinsic ion channels that allow the neurons to fire spontaneously.⁶⁸ Purkinje cells express several classes of voltage-gated calcium channels such as the P/Q type calcium, T-type calcium, and calcium-activated potassium channels (SK channels) that contribute to burst firing.⁶⁹ (Figure 2)

Figure 1:

Climbing fibers synapse with Purkinje cell dendrites. In the presynaptic terminal, activation of P/Q-type calcium channels releases excitatory neurotransmitters, leading to the firing of the Purkinje cell. In the postsynaptic membrane, activation of T-type calcium channels and inhibition of calcium-activated potassium channels (SK channel) or GABA receptor activity leads to increase in Purkinje cell firing.

Figure 2:

Purkinje cell firing and spikes. High threshold depolarization is depolarization when the rest membrane potential is more negative compared to the threshold (A); low threshold depolarization is depolarization when the rest membrane potential is less negative compared to the threshold (B); subthreshold oscillations are fluctuations occurring below the threshold potential (C); simple spike is a single spike (D); complex spike is a stereotyped burst of decrementing spikes (E).

Reducing hyperexcitability of Purkinje cell and other hyperexcitable neurons

Targeting P/Q type calcium channels in essential tremor

The P/Q-type calcium channel (also referred to as Ca_v2.1) is a presynaptic high-voltage-gated calcium channel, which couples neuronal excitation to the secretion of neurotransmitters.⁷⁰ The ion-conducting pore is formed by four domains of the α_1A subunit, whereas accessory subunits (β, α2δ) modulate channel kinetics and the level of expression on the neuronal membrane. Although P-type currents are mainly identified in Purkinje cells⁷¹ and Q-type currents are identified in cerebellar granule neurons,⁷² they are referred together as P/Q-type channels since the distinction between these channels is not always clear.

Primidone, topiramate, gabapentin, pregabalin, and levetiracetam interact with P/Q-type calcium channels. While the exact mechanism of action in essential tremor is not completely elucidated, primidone alters the functions of transmembrane P/Q-type calcium channels. Phenobarbital is a metabolite of primidone that increases the duration of GABA receptor opening but plays a lesser role in the therapeutic control of tremor.⁷³ Clinical studies, including double-blind placebo-controlled trials, have shown consistent improvements in the patient-reported, physician-based, and electrophysiologic assessments.^74–76 However, the overall efficacy is in the range of 50 – 60% improvements and multiple adverse effects, including the first dose acute toxic reaction, sedation, daytime sleepiness, tiredness, nausea, ataxia, dizziness, and confusion, frequently leads to discontinuation of the therapy.⁷⁷

Unlike clonazepam and alprazolam which have pure GABAergic actions, topiramate has multiple actions, including augmenting activity at the GABA_A receptors, antagonizing the glutamate receptors, and inhibiting the carbonic anhydrase enzyme.⁹ Topiramate also blocks voltage-gated sodium channels and P/Q-type calcium channels. It remains unknown which of these mechanisms play the key role in tremor control. Many randomized placebo-controlled studies involving a total of more than 300 patients found topiramate as an effective monotherapy or as an add-on treatment.^78–80 There is an overall 30 – 40% reduction of tremor with paresthesia, concentration/attention difficulty, appetite suppression/weight loss, and nausea, which are among the most common adverse events.⁷⁷

Then, gabapentin, an inhibitory neurotransmitter in the brain, was developed as a structural analog of gamma-aminobutyric acid (GABA). However, gabapentin does not bind to GABA_A or GABA_B receptors.⁸¹ Instead, it interacts with the α2δ subunit of the presynaptic voltage-gated P/Q-type calcium channels leading to reduced neurotransmitters in the synaptic space.⁸² Despite high lipophilicity and easy crossing of the blood-brain barrier, clinical studies have revealed mixed efficacies.⁸³ While one study found a nearly 40 – 50% reduction of tremor amplitude, other trials did not confirm these findings.^{84 85} Moreover dosing at 1200 – 3600mg was found to lead to side effects such as sleepiness, dizziness and nausea in a third of patients. Pregabalin is another GABA analog that also has no affinity to GABAergic receptors,⁸⁶ but binds to α2δ subunit of voltage-gated calcium channels. Although pregabalin can reduce neuronal hyperexcitability theoretically, clinical studies did not reveal significant benefits. Similarly, the use of levetiracetam (an antiepileptic drug) did not lead to a consistent reduction of tremor.⁸⁷ A recent systematic review concluded that topiramate was efficacious; however, the limiting factors were side effects such as appetite suppression, weight loss, cognitive impairment, and paresthesia. While gabapentin lacked sufficient evidence pregabalin and levetiracetam did not reveal significant benefits for the treatment of essential tremor.⁷⁷

Targeting T-type calcium channels

T-type voltage-gated calcium channels were identified around three decades ago. Three distinct isoforms of T-type calcium channels, Ca_v 3.1, 3.2, and 3.3⁸⁸ are expressed in cerebellar motor circuits.^{89 90 91} Of particular importance is Ca_v3.1 subtype which is highly expressed in the tremor network.⁹² Dendrites of Purkinje cell show a high density of voltage-gated calcium channels⁹³ Khodakhah et al. have shown that the dendritic calcium spike is the key factor leading to a spontaneous burst firing of Purkinje cells. T-type calcium channels with a low threshold for activation⁹⁴ reveal a tendency to generate a spontaneous rhythmic subthreshold oscillations (STO) of the neuronal membrane. These subthreshold oscillations can potentially convert to rhythmic 9–12 Hz burst-firing.²⁸ A low threshold for activation also leads to the generation of low-threshold spikes (LTS) of calcium and sodium.^{95 96} Hyperpolarization of the neuronal membrane increases the possibility of generation of LTS through activation of the T-type calcium channels. LTS regulates neural oscillations, resonance,^{29 95} and synchronous firing of multiple neurons. The membrane threshold is easily pushed by the LTS to generate the next spike and ultimately the development of bursts of action potentials.⁹⁷ Each burst developed with an increase in firing rate is terminated by a more rapid increase in firing rate and a decrease in spike height. Electrical coupling between multiple neurons leads to the formation of ensembles and clusters.^{98 99} Patch clamp recordings have found that harmaline exposure under certain physiological conditions leads to net potentiation of T-type calcium channel.³⁰ Thus, drug compounds directed against Ca_v3.1 subtype are highly desirable to control the Purkinje cell firing.

Despite conflicting data from early mouse model experiments, several studies pursued development of compounds targeting T-type calcium channels.^{92 100 101} Ethosuximide and zonisamide, antiepileptic drugs were initially considered as potential therapeutic agents as they had antagonistic properties against T-type calcium channels.¹⁰² Ethosuximide was primarily examined in the MPTP primate model¹⁰³ and the rat model for parkinsonian tremor.¹⁰⁴ Unfortunately, clinical studies revealed mostly null results.^{105 106} While the initial data with zonisamide was promising a subsequent study that was double-blind and placebo-controlled did not confirm the clinical benefits.^{107 108 109 110 111} The double-blind and placebo-controlled study was small; it included patients with mild tremor severity and did not achieve adequate dosing with careful escalation was not achieved; thus, precluding a definitive conclusion. Future studies with larger cohorts are warranted to investigate the role of zonisamide further. Flunarizine is another T-type calcium channel blocker prescribed for migraine and vertigo and was tried in multiple small studies in patients with essential tremor.^{112 113} Overall the drug was found to be ineffective with studies, reporting drug induced movement disorders (orofacial dyskinesia and parkinsonism) in nearly 30% of patients.^{114 115 116}

Many patients with essential tremor report that ingestion of small amounts of alcohol leads to improvements of tremor.¹¹⁷ Objective assessments have revealed that nearly 50% of patients demonstrate an improvement when subjected to an alcohol challenge test.¹¹⁸ Alcohol effects are mainly mediated through the GABA receptors located in extra synaptic neuronal membrane and some through the T-type calcium channels located in postsynaptic neuronal membrane. Acute ethanol administration has been shown to disrupt the native calcium currents from activation of T-type calcium channels (Ca_V 3.2 isoform).^{119 120} Chronic exposure to intermittent ethanol followed by withdrawal can also disrupt calcium channel expression and function.¹²¹

Although ethanol leads to tremor improvement, the dose required for beneficial effects has been found to be close to the dose needed for inducing toxicity effects (a narrow therapeutic range).¹¹⁷ But 1-octanol, the long-chain version of alcohol, was found to reduce tremor without causing intoxication or other clinically relevant adverse effects.¹²² In a placebo-controlled trial involving 12 essential tremor patients, a single dose (1mg/kg) of 1-octanol was found to lead to a distinct taste of orange peel. The side effect of dysgeusia was expected as the 1-octanol compound is a natural flavoring substance present in orange peel.¹²³ Overall, 1-octanol is well tolerated, but the benefits last only 15 to 90 minutes and relatively large volumes are necessary to formulate capsules for oral administration, thus further studies do not seem to be feasible.¹¹⁷

Octanoic acid, a metabolite of 1-octanol and approved as a food additive has better pharmacokinetics.¹¹⁷ Since the bioavailability is nearly 100%, lower oral dose is needed compared to the 1-octanol compound.^{124, 125} After revealing benefits in the harmaline model for essential tremor, octanoic acid was examined in a pilot cohort of essential tremor. The drug tolerated at a low dose (4 mg/kg) was observed to reduce tremor on the accelerometer-based assessment but there was no improvement in patient-reported activities of daily living and the digital spiral analysis.¹²⁶

Recently, CX-8998 a compound was developed that has a specific potency against Ca_v3 subtype of T-type calcium channels.¹²⁷ The compound at single and multiple doses in healthy volunteers and patient populations had revealed adequate safety. Following the promising efficacy in early clinical studies, a phase 2 proof of concept study was launched in essential tremor comparing an active group (n = 39) with a placebo (n = 44) group. Patients with moderate to severe tremor severity were randomized 1:1 to CX-8998 and placebo groups. The CX-8998 compound was titrated to 10mg twice a day for 4 weeks. The primary endpoint was the change from baseline in the blinded video ratings of the Essential Tremor Rating Assessment Scale performance subscale scored by two groups of raters. The first group comprised experts from the tremor research group (central raters) and the other group comprised the investigators from the individual sites. Secondary outcomes included blinded live ratings of The Essential Tremor Rating Assessment Scale performance subscale, assessment of the activities of daily living and tremor severity with Kinesia ONE accelerometry. Overall the study revealed mixed findings. The central ratings of the videos were not significant but the investigator ratings were statistically significant (p = 0.017). The patients reported improvements in the activities of daily living (p = 0.049) but the objective sensor-based assessment was not significant (p = 0.421). Dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%) were common adverse effects reported by the participants.¹²⁸

Targeting Potassium channels

Calcium-activated potassium (SK) channels are widely distributed in the central nervous system. While P/Q-type and T-type voltage-gated calcium channels contribute to burst firing of the Purkinje cells, SK channels contribute to interspike and interburst intervals and termination of burst firing.^{69 100} In one study, partial block of P/Q-type calcium channels led to elimination of calcium spikes and caused a switch from regular bursting to tonic firing or irregular bursting.¹²⁹ An increase in intracellular calcium activates these channels which leads to potassium efflux, thereby repolarizing or hyperpolarizing the synaptic membrane. The synaptic levels of SKs and their sensitivity to calcium levels are regulated by protein kinases and phosphatases.¹⁰⁰ These channels play a critical role in synaptic transmission and thus in transmitting information along the neuronal circuits expressing them. These channels are key for learning, memory, and rhythmic activities in synaptic plasticity. In the context of essential tremor, an increased function of SK channels would lead to an overall reduced and regularized firing of neurons within the tremor network.¹³⁰ SKs are critically involved in coordinating diverse calcium signaling pathways and controlling calcium signal amplitude and duration.¹³⁰ In a recent open-label study, CAD-1883, a compound with positive allosteric modulation of the SK channel, was tested to evaluate the safety, tolerability, and efficacy. The oral compound was administered twice daily to adult participants with essential tremor to increase the sensitivity of SK channels to calcium (ClinicalTrials.gov Identifier: NCT03688685). The trial results will pave a novel pathway for targeting the Purkinje cell hyperexcitability.

Finally, hyperpolarization-activated cyclic nucleotide-gated (HCN) channel channels are cation channels in the voltage-gated potassium channel superfamily.¹³¹ In a rat model study, a missense mutation in the Hcn1 gene that led to activation of these channels resulted in membrane hyperpolarization and tremor oscillations. The tremor phenotype of these rats was similar to essential tremor. Propranolol was found to lead to alleviation of tremor though modulation of HCN channels. It is postulated that the central mechanism of action for this drug involves the HCN channel but further studies are needed for definitive evidence.¹³²

Targeting for optimal therapy.

In summary, the last decade has seen a significant increase in the pathophysiological understanding of essential tremor. Growing evidence supports that the inferior olivary nucleus may not play as important a pathogenic role as previously thought. Instead, a defective climbing fiber afferent input leading to Purkinje cell burst firing is likely the key component of the pathophysiological network. Purkinje cells express several voltage-gated calcium channels and potassium channels that contribute to burst firing, such as the P/Q-type, T-type, and SK channels. As summarized in Figure 3, treatment for essential tremor involves either reducing the activation of calcium channels or increasing the functions of SK channels. The older drugs, including the primidone and topiramate, have partial actions against the P/Q-type channels in the Purkinje cell dendrites. Primidone and topiramate also potentiate GABA receptor activation in the dentate neurons which is another important contributor to pathophysiology. The current drugs available for clinical use frequently lead to less than 50% control of symptoms with many dose-limiting side effects. There is mounting preclinical evidence to show that an increased T-type calcium channel activation and a reduced SK channel activation are critical for the hyperexcitability of the Purkinje cell neurons. Thus, many new drug developments in the pipeline are focusing on the T-type calcium channel and SK channel activity. These next generations of drugs will likely lead to more effective tremor control with greater tolerance and a lower risk of undesirable side effects.

Figure 3:

Drugs reducing the calcium channel functions or increasing the SK channel or the GABA receptor functions are shown in the figure. A balance of activation will lead to effective tremor suppression.