From the Molecular Mechanism to Pre-clinical Results: Anti-epileptic Effects of Fingolimod

Abstract

Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2 % of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders. Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.

Keywords: Epilepsy; S1P receptor; drug repurposing; fingolimod; neuroinflammation.

Fig. (1)

Molecular mechanisms associated with the disease-modifying anti-epileptic effects of Fingolimod. Experimental evidence indicates the disease-modifying anti-epileptic effects of Fingolimod against epileptic seizures. The underlying molecular mechanisms involve primarily its anti-neuroinflammatory effects as evident by a reduced level of TNF-α, IL-1B, NF-κB, and COX-2. Moreover, Fingolimod confers significant neuroprotection by reducing neuronal cell loss as evident by increased NeuN-positive cells and decreased FJB-positive cells. It was further shown to activate/modulate S1PR1 and SP1R3 during epileptic seizures as well as reduce the activation of astrocytes and microglia (as evident by GFAP and IBA1 positive cells). Moreover, Fingolimod can downregulate the activation of mTOR pathway leading to decreased p-mTOR, p-p70S6k and elevated p-AKT levels. Increased staining of myelin staining, as well as OPCs, have also been observed upon treatment with Fingolimod reflecting its potential for myelin repair. GFAP, Glial fibrillary acidic protein; IL, Interleukin; IBA1, Ionized calcium-binding adapter molecule 1; COX-2, Cyclooxygenase-2; NF-κB, Nuclear factor κ light chain enhancer of activated B cells; TNF-α, Tumour necrosis factor-α; OPCs, Oligodendrocyte precursor cells; S1P, Sphingosine-1-phosphate; S1PR1, S1P receptor 1; S1PR3, S1P receptor 3; mTOR, Mammalian target of rapamycin; AKT, Protein kinase B. (A higher resolution / colour version of this figure is available in the electronic copy of the article).