Chronic intermittent hypoxic preconditioning suppresses pilocarpine-induced seizures and associated hippocampal neurodegeneration

• We compared the antiseizure efficacies of two hypoxic preconditioning protocols.
• Both normobaric and hypobaric protocols suppressed pilocarpine-induced seizures.
• Both protocols reduced post-ictal [Ca2+]i elevations and neuronal death.
• However, hypobaric preconditioning was more effective.

Mild brief hypoxia can protect against neuronal damage induced by epileptic seizures, at least in part by inhibiting apoptosis. Further elucidation of the antiepileptic mechanisms and optimization of the conditioning protocols are required before this strategy can be considered for clinical intervention. In this study, we compared the effects of different hypoxic preconditioning protocols on spontaneous recurrent seizures (SRS), intracellular free calcium concentration ([Ca2+]i), and apoptosis rate following pilocarpine-induced status epilepticus (SE). Male Sprague Dawley rats were subjected to either chronic intermittent hypobaric hypoxia (CIHH) or chronic intermittent normobaric hypoxia (CINH) (both for 6 h/day×28 consecutive days) prior to pilocarpine-induced SE. The possible anticonvulsant and neuroprotective effects of CIHH and CINH were compared by video monitoring of behavioral seizure activity (frequency, delay), Nissl staining and Fluoro-Jade B (FJB) staining to examine changes in the morphology of hippocampal pyramidal neurons, and flow cytometry to detect the quantification of [Ca2+]i and cell apoptosis. Both hypoxic preconditioning protocols reduced the frequency and severity of SRS, suppressed post-ictal [Ca2+]i elevations, and inhibited neuronal apoptosis in the rat hippocampus compared to pilocarpine alone, but CIHH was more effective than CINH. Thus, mild hypoxic pretreatment, particularly when delivered as CIHH, may be a novel strategy for the clinical prevention and treatment of epilepsy.