Aminopiridines in the Treatment of Multiple Sclerosis and Other Neurological Disorders

Abstract

Symptomatic treatment has a great relevance for the management of patients with neurologic diseases, since it reduces disease burden and improves quality of life. Aminopyridines (APs) are a group of potassium (K+) channel blocking agents that exert their activity both at central nervous system level and on neuromuscular junction. This review describes the use of APs for the symptomatic treatment of neurological conditions. We will describe trials leading to the approval of the extended-release 4-aminopyridine for MS and evidence in support of the use in other neurological diseases.

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury

“…It is perhaps more important that repurposing of 4-AP for examination in these traumatic injuries is more straightforward. Due to the long-standing interest in the use of 4-AP in treating multiple chronic neurological problems (including MS, nystagmus, Lambert-Easton myasthenic syndrome and spinal cord injury), extensive information exists regarding appropriate dosage regimens, side-effects and other concerns related to translation of studies from the laboratory to the clinic [ 17 ]. Studies on diagnosis and recovery from peripheral nerve injury have already led to two clinical trials on 4-AP treatment of acute injuries [ 28 , 29 ].…”

“…4-AP is a small molecule inhibitor of voltage-gated potassium (Kv) channels that readily crosses the blood–brain barrier yet has an uncertain mode of action in patients [ 20 , 34 ]. In MS and other chronic neurological diseases, 4-AP is thought to enhance action potential conduction and modulate overall neural circuit activity through inhibiting aberrant Kv currents of axons and/or amplification of synaptic transmission [ 17 , 69 , 87 ]. Therapeutically, low dose (10 mg, twice daily) extended release 4-AP (dalfampridine) is effective at blood levels below 100 ng/ml (~ 1 µM) without unacceptable adverse effects, particularly seizure induction [ 34 ].…”

4-aminopyridine promotes accelerated skin wound healing via neurogenic-mediator expression

“…The utilization of 4-AP to promote tissue repair is a qualitatively new use for this wellstudied and clinically-utilized drug. The positive tissue regenerative effects of 4-AP in the skin are very novel from the extensively studied ability of this drug to provide transient symptomatic relief, without evidence of regenerative changes, in chronic neurological illnesses and injuries as multiple sclerosis, myasthenia gravis, cerebellar gait ataxias, downbeat and upbeat nystagmus and spinal cord injury (e.g., (91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106)). In neurological cases, the behavioral benefits of 4-AP are lost when treatment is terminated and the drug is cleared from the body.…”

“…The ability to accelerate skin wound healing and skin regeneration is novel. Extensive prior studies on 4-AP safety and dosing (e.g., (24, 26, 92, 93, 99, 117)), and its FDA approval in 2010 for the treatment of multiple sclerosis, make the transition of this compound from laboratory back to the clinical arena for wound healing therapy relatively straightforward. Indeed, our findings that 4-AP treatment can be used to distinguish between incomplete and complete peripheral nerve injuries have already transitioned to clinical trials on the diagnosis of such injuries (https://clinicaltrials.gov/ct2/show/NCT04026568)(17, 20).…”

Acute Axon Damage and Demyelination are Mitigated by 4-Aminopyridine (4-AP) Therapy after Experimental Traumatic Brain Injury

“…4-AP is a small molecule inhibitor of voltage-gated potassium (Kv) channels that readily crosses the blood-brain barrier yet has an uncertain mode of action in patients (Goodman and Stone, 2013; Dietrich et al, 2021). In MS and other chronic neurological diseases, 4-AP is thought to enhance action potential conduction and modulate overall neural circuit activity through inhibiting aberrant Kv currents of axons and/or synapses (Smith et al, 2000; De Giglio et al, 2020). Therapeutically, low dose (10 mg, twice daily) extended release 4-AP (dalfampridine) is effective at blood levels below 100 ng/ml (∼ 1 μM) without unacceptable adverse effects, particularly seizure induction (Goodman and Stone, 2013).…”