Effects of PRI-2191—A low-calcemic analog of 1,25-dihydroxyvitamin D 3 on the seizure-induced changes in brain gene expression and immune system activity in the rat

Abstract

Apart from the essential role of 1α,25-dihydroxyvitamin D 3 in calcium and phosphorus metabolism, this compound and its analogs are involved in regulating the functions of the central nervous and immune systems. Active forms of vitamin D 3 have been reported to stimulate neurotrophin gene expression and to prevent neuronal damage against a variety of insults. In the present study, we evaluated the effects of PRI-2191—a low-calcemic analog of 1α,25-dihydroxyvitamin D 3 (50 ng/kg i.p., once daily for 8 days) on seizure-related neuronal degeneration, changes in some brain gene expression and immune system activity. Seizures were induced by pilocarpine (400 mg/kg; i.p.) administration. An in situ hybridization study showed that the pilocarpine-induced seizures led to time-dependent changes in the brain-derived neurotrophic factor (BDNF), heat shock protein 70 (HSP-70) and prepro-thyreoliberin (prepro-TRH) gene expression in several cortical and hippocampal regions. The maximal induction of gene expression was 3 h for BDNF and 24 h for HSP-70 and prepro-TRH; however, only in the case of prepro-TRH that effect was long-lasting. PRI-2191 alone had no effect on gene expression, but it enhanced the seizure-evoked expression of HSP-70, had an opposite effect on BDNF mRNA level and did not affect prepro-TRH mRNA level. Moreover, PRI-2191 had a moderate inhibitory effect on the seizure-related hippocampal damage in the CA1 field only. An immunological study revealed that PRI-2191 reversed the seizure-induced decrease in the proliferative activity of splenocytes and their ability to produce interferon-γ. Summing up, the present study demonstrated that subchronic administration of PRI-2191 significantly modulated the seizure-related changes in both the brain and the peripheral immune system of rats.