Ketogenic Diet Alleviates Hippocampal Neurodegeneration Via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy

Abstract

The ketogenic diet (KD) is a proven therapy for refractory epilepsy. Although the anti-seizure properties of this diet are understood to a certain extent, the exploration of its neuroprotective effects and underlying mechanisms is still in its infancy. Tissue acidosis is a common feature of epileptogenic foci. Interestingly, the activation of acid-sensing ion channel 1a (ASIC1a), which mediates Ca²⁺ -dependent neuronal injury during acidosis, has been found to be inhibited by ketone bodies in vitro. This prompted us to investigate whether the neuroprotective effects induced by the KD occur via ASIC1a and interconnected downstream mechanisms in a rat model of temporal lobe epilepsy. Male Sprague-Dawley rats were fed either the KD or a normal diet for four weeks after undergoing pilocarpine-induced status epilepticus (SE). During the chronic period following SE, we found that the KD treatment strongly attenuated the spontaneous recurrent seizures, ameliorated learning and memory impairments and prevented hippocampal neuronal injury and apoptosis. The KD was also shown to inhibit the upregulation of ASIC1a and the ensuing intracellular Ca²⁺ overload in the hippocampus of the epileptic rats. Furthermore, the seizure-induced structure disruption of neuronal mitochondria, loss of mitochondrial membrane potential and accumulation of mitochondrial reactive oxygen species were reversed by the KD treatment, suggesting that it has protective effects on mitochondria. These findings, together with the inhibition of caspase-3 activation, indicate that the KD suppresses mitochondria-mediated apoptosis by regulating ASIC1a to exert neuroprotective effects. This may provide a mechanistic explanation of the therapeutic effects of KD.

Note:
Funding Information: This work was supported by the Natural Science Foundation of Hebei Province (H2018206435).

Declaration of Interests: None.

Ethics Approval Statement: All experiments were approved by the Research Ethics Committee of the Second Hospital of Hebei Medical University and were performed in accordance with the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals.

Keywords: ketogenic diet, temporal lobe epilepsy, Acid-sensing ion channel 1a, Mitochondrial pathway, neuroprotection