4-aminopyridine and acetyl-DL-leucine for treating cerebellar disorders

 4-aminopyridine (4-AP, fampridine, dalfampridine) has been used to treat episodic ataxia 2 and downbeat nystagmus; so far it does not seem to have been trialed or even suggested for use in multiple system atrophy:

"In recent years, advance has been made in the pharmacological treatment of cerebellar disorders, for example episodic ataxia type 2 (EA2) and in adition downbeat nystagmus (DBN), specifically because of the utilization of aminopyridines (AP) [-]. This agent is a nonselective blockers of the Kv family, mainly the Kv1.5 voltage-activated potassium channels, thereby prolonging the duration of action potentials in axons because of delayed repolarization []. In vitro studies showed that 4-aminopyridine (4-AP) increases the resting discharge rate and excitability of cerebellar Purkinje cells (PCs) of the guinea pig cerebellum [], and regulates the PC firing in brain slices of the rat [, ], Due to an increased activity of PC [] the GABAergic inhibitory influence on the deep cerebellar nuclei mediated by the vestibulo-cerebellum is restored. This is assumed to be the mechanism behind the therapeutic influence of AP in cerebellar disorders. This increased inhibitory influence has been confirmed by findings in patients with ataxia telangiectasia, where the ingestion of 10 mg 4-AP resulted in a shortened time constant of the angular vestibulo-ocular reflex (VOR) []. Clinically, both 4-AP and 3,4-diaminopyridine (3,4-DiAP) are currently used but for different indications: 4-AP in central nervous disorders because it better penetrates the blood-brain barrier [] and 3,4-DAP in Lambert-Eaton myasthenic syndrome (LEMS). In an animal model of EA2 (tottering mouse), 4-AP restored the decreased accuracy of pacemaking in PCs by prolonging the action potential and expanding the action potential after hyperpolarization []. Furthermore, 4-AP and 3,4-DiAP, reduced the frequency of restraint- and caffeine-induced attacks in the tottering mouse, by increasing the threshold for the attacks []."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341500/ 

The article also discusses acetyl-DL-leucine (which is why it looked it up in the first place); unfortunately there is study that found no benefit for MSA:

 https://pubmed.ncbi.nlm.nih.gov/28716222/

 - at least that is what is related in the title of the article. No abstract is available and the article is paywalled. I have requested a copy through ResearchGate, but I doubt I will get a response. 


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