Blocking hippocampal voltage-gated potassium channel Kv1.3 by dalfampridine abrogates cognitive impairment in experimental autoimmune encephalomyelitis mouse model.

Multiple sclerosis (MS) is devastating motor disorders accompanied by cognitive impairments. Dalfampridine (Dal), was approved for treating MS via blocking voltage-gated potassium channel (Kv). Kv1.3 is one of Dals' targets that showed insults to cognitive function in preclinical and clinical cases. Yet, there is no study that has assessed the potentiality of Dal on Kv1.3-induced cognitive impairment in MS. Thus, the aim of the present study is to reveal the procognitive influence of Dal in the MS animal model. Mice were randomly assigned into four groups. Saline was administered to group 1, conversely groups 2, 3, and 4 received 2 shots of rat spinal cord emulsified with complete Freund's adjuvant. Group 3 received Dal (10 μg/mouse; p. o), while group 4 received Wortmannin (0.1 μg/mouse; i. c.v), a selective phosphoinositide 3-kinases (PI3K) inhibitor, before Dal administration. After 14 days, Dal alleviated motor deficits in the open field arena and rotarod with cognitive restoration in the novel object recognition task. These were accompanied by the reversal of hippocampal neuronal loss and demyelination in corpus callosum. Additionally, Dal inhibited Kv1.3 that enhanced survival signaling, viz; PI3K/Akt. Such activation abates neuroinflammatory markers, glycogen synthase kinase-3 beta (GSK-3β) and nuclear factor-κB levels with subsequent enhancement of BDNF. All these amendments were reversed by Wortmannin pre-administration. In conclusion, this study declares that blockade of Kv1.3 and modulation of PI3K/Akt/GSK-3β/BDNF axis with Dal could be proposed as a promising neuroprotective and memory-enhancing treatment in MS.