Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin and carbamazepine

Abstract

These results, together with results showing effects of sodium channel blockers in immune cells, raise questions about the long-term effects of sodium channel blockers in neuroinflammatory disorders, and suggest that clinical studies of sodium channel blockers in these disorders should be planned carefully.

Regulation of Podosome Formation in Macrophages by a Splice Variant of the Sodium Channel SCN8A

“…Prior studies of sodium channel blockers such as phenytoin and carbamazepine in the rodent model of multiple sclerosis, experimental autoimmune encephalomyelitis, demonstrated efficacy in reduction of disease severity (30 -32). Although these results were originally hypothesized to be due to a direct protective effect on neuronal axons, the present results combined with the rapid inflammatory rebound effect seen following withdrawal of these agents (8) suggest an anti-inflammatory effect in addition to a neuroprotective one (33). A similar mechanism of action of sodium channel blockade also may be relevant in tumor cell biology.…”

“…NaV1.6 has a less clear functional role in macrophages. Unlike NaV1.5, NaV1.6 is also expressed in unprimed human macrophages and in unprimed and primed mouse macrophages and microglia (7,8). Many invasive neoplastic cell lines also express voltage-gated sodium channels, which may regulate their ability to metastasize (9).…”

Ion channels in autoimmune neurodegeneration

“…Inhibition of sodium channel function using specific blockers revealed that two distinct blockers, phenytoin and carbamazepine, significantly improved the clinical course of the disease. However, withdrawal of treatment resulted in acute exacerbation, accompanied by a significantly increased inflammatory infiltrate within the central nervous system and the death of nearly 60% of phenytointreated and 8% of carbamazepine-treated EAE mice [52]. In a phase 2 trial, the neuroprotective role of lamotrigine, a partial sodium channel blocker, was tested in patients with secondary progressive multiple sclerosis (SPMS).…”

“…However, lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment [53]. Another clinical trial with phenytoin in patients with primary progressive MS was planned, but due to the clinical worsening after withdrawal in the animal study mentioned above [52], the study was never initiated [54,55]. Although the findings in pre-clinical studies pointed to an effective mechanism to ameliorate MS symptoms, sodium channel blockers by now missed the clinical translation due to the rebound effect after discontinuation of the drug.…”

Neurodegeneration in multiple sclerosis: novel treatment strategies

“…Evidence from animal studies has shown beneficial effects in rats with chronic EAE for up to 180 days after treatment with phenytoin [120], a Na + channel blocker commonly used for epilepsy. Interestingly, when the study was repeated using either phenytoin or carbamazepine, another antiepileptic with Na + channel blocker capacities, the animals became acutely worse after the withdrawal of either drug [121], indicating that more work needs to be done to understand the consequences of the long-term effects of Na + channel blockers and of their withdrawal in MS. Two other Na + -blocking agents, the antiarrhythmic agent flecainide and the antiepileptic lamotrigine, have now been shown to improve axonal survival and decrease disability in EAE-affected rats [122,123]. However, in a Phase II study in patients with secondary progressive disease course, lamotrigine showed an increase of cerebral volume loss which was not clinically relevant, but could not be explained [123].…”