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Blocking hippocampal voltage-gated potassium channel Kv1.3 by dalfampridine abrogates cognitive impairment in
Heba Nasr Shalaby1, Dalia A Nawwar1, Ahmed S Kamel2
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Abstract:
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.
Insights
Dalfampridine (Dal) improves motor and cognitive deficits in a multiple sclerosis (MS) animal model by blocking Kv1.3 channels. This treatment enhances neuronal survival pathways, offering a potential neuroprotective therapy for MS patients.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Multiple sclerosis (MS) is a debilitating neurological disorder characterized by motor and cognitive impairments.
- Voltage-gated potassium channel Kv1.3 is implicated in MS-related cognitive dysfunction.
- Dalfampridine (Dal) is an MS therapeutic agent targeting potassium channels, but its effect on Kv1.3-induced cognitive deficits in MS is unstudied.
Purpose of the Study:
- To investigate the procognitive effects of Dalfampridine (Dal) in an animal model of multiple sclerosis (MS).
- To elucidate the role of Kv1.3 channel blockade and associated signaling pathways in Dal's therapeutic action.
Main Methods:
- An experimental autoimmune encephalomyelitis (EAE) model of MS was induced in mice.
- Mice received saline, EAE induction, or EAE induction plus Dalfampridine (Dal) or Wortmannin (a PI3K inhibitor) followed by Dal.
- Motor function was assessed using open field and rotarod tests; cognitive function was evaluated via novel object recognition task.
Main Results:
- Dalfampridine (Dal) significantly alleviated motor deficits and restored cognitive function in the MS model.
- Dal treatment reversed hippocampal neuronal loss and demyelination in the corpus callosum.
- Dal inhibited Kv1.3, activating the PI3K/Akt survival pathway, reducing neuroinflammation (GSK-3β, NF-κB), and increasing BDNF levels.
- Wortmannin pre-administration blocked the beneficial effects of Dal, confirming the involvement of the PI3K/Akt pathway.
Conclusions:
- Dalfampridine (Dal) demonstrates neuroprotective and memory-enhancing effects in an MS animal model.
- Kv1.3 channel blockade by Dal modulates the PI3K/Akt/GSK-3β/BDNF signaling axis.
- Dal's mechanism involves enhancing neuronal survival and reducing neuroinflammation, suggesting its potential as a novel MS therapeutic strategy.
