Effects of PRI-2191-A low-calcemic analog of 1,25-dihydroxyvitamin D3 on the seizure-induced changes in brain gene expression and immune system activity in the rat

Apart from the essential role of 1α,25-dihydroxyvitamin D3 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 D3 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 D3 (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.