tacrolimus and trimethyltin

There is little information on the molecular mechanisms in FK506-mediated neuroprotection. In the present study, we investigated the protective effect of FK506, an immunosuppressant and neuroprotectant, on trimethyltin (TMT)-induced neurotoxicity in the rat hippocampus. Histologically, TMT-induced neuronal damage was partially prevented by FK506 in the hippocampal CA1 region, but not in CA3. FK506 treatment significantly reduced the number of apoptotic cells in CA1, but not in CA3, and also prevented induction of cognitive deficits by TMT. Microarray analysis of the rat hippocampus detected 14 genes with TMT-induced alteration of mRNA expression that was rescued by FK506 treatment. Subsequent quantitative RT-PCR analysis confirmed elevated mRNA levels for four inflammatory genes, glutathione S-transferase, lysozyme, matrix Gla protein, and osteopontin after TMT treatment. Upregulation of these genes was reversed by FK506 treatment at 5 days postgavage. Immunohistochemistry revealed that FK506 reduced osteopontin (OPN) induction by TMT in the periarterial area at 5 days postgavage. Our data suggest that inflammatory gene expression is involved in TMT-induced damage to the hippocampal CA1 region, resulting in apoptosis, and that this process is initiated by periarterial OPN activation, and can be alleviated by FK506.

Topics: Analysis of Variance; Animals; Apoptosis; Behavior, Animal; Disease Models, Animal; Drug Interactions; Gene Expression Regulation; Hippocampus; Immunosuppressive Agents; In Situ Nick-End Labeling; Male; Microarray Analysis; Neurotoxicity Syndromes; Osteopontin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tacrolimus; Time Factors; Trimethyltin Compounds

FK506, originally classified as an immunosuppressant, may also be implicated in some events in the central nervous system. FK506 elicits both neuroprotective and neurotrophic effects in vitro. FK506 is neuroprotective for focal cerebral ischemia, but it is not clear whether FK506 has neuroprotective effects for other brain diseases. In this study, we investigated possible neuroprotective effects of FK506 in experimental temporal lobe epilepsy (TLE) induced by kainic acid (KA) or trimethyltin (TMT). In rat models, we observed marked protection against seizures, abnormal behaviors, and accompanying delayed neuronal damage in the hippocampus by the systemic injection of FK506.

Topics: Aggression; Animals; Anticonvulsants; Cell Survival; Dose-Response Relationship, Drug; Epilepsy, Temporal Lobe; Excitatory Amino Acid Agonists; Immunosuppressive Agents; In Situ Nick-End Labeling; Kainic Acid; Male; Rats; Rats, Sprague-Dawley; Seizures; Tacrolimus; Trimethyltin Compounds