Abstract: P863

Type: Poster

Abstract Category: Experimental models

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). MS is characterized by the impairment of axonal transmission and the reduction in nerve conduction velocity, resulting neurological and motor deficits. Fampridine is approved as a treatment to improve walking in MS. It is thought that fampridine improves walking in MS patients by blocking potassium channels, thereby improving nerve impulses across regions of demyelination in axons. In a mouse model of MS, fampridine has been shown to ameliorate gait deficits but did not alter the disease course¹. Amantadine HCl is an NMDA receptor (NMDAr) antagonist approved for the treatment of influenza infection and Parkinson's disease. In addition to its glutaminergic activity, amantadine has also been shown to modulate other neurotransmitter systems, inhibit microglial activation, and elevate levels of brain-derived neurotrophic factor (BDNF). Amantadine has been shown in clinical trials to reduce fatigue in MS, but its effects on gait and walking have not been evaluated. Here, we characterize the in vitro effects of amantadine on potassium channel activity and the efficacy of amantadine in a mouse model of MS. First, we compared the effects of amantadine to fampridine on the blockade of potassium currents in rat coronal brain slices. Both amantadine and fampridine blocked potassium leak currents and delayed rectifying currents in a concentration-dependent fashion, but potassium current blockade occurred at 10-100 fold lower concentration with amantadine compared to fampridine. Next, we assessed the effects of amantadine in experimental autoimmune encephalomyelitis (EAE), a mouse chronic model of MS. EAE was induced in female C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG_35-55), and disease severity and gait parameters were measured over 28 days. We found that chronic administration of clinically relevant doses of amantadine reduced the severity of clinical disease, improved gross motor function and improved walking following EAE in mice. Together, the data suggest that amantadine may have clinical utility as treatment in MS, and provide a framework for further clinical evaluation.

References: ¹Gobel et al. (2013) 4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis, Experimental Neurology, 248: 62.

Disclosure:

This study was funded by Adamas Pharmaceuticals.

Jack Nguyen: employee and stock holder of Adamas Pharmaceuticals

Elizabeth Brigham: employee and stock holder of Adamas Pharmaceuticals

Juho Oksman: received funding from Adamas Pharmaceuticals

Toni Ahtoniemi: received funding from Adamas Pharmaceuticals

Bogdan Sava: received funding from Adamas Pharmaceuticals

Bruno Buisson: received funding from Adamas Pharmaceuticals