Chronic treatment with a selective ligand for the sigma-1 receptor chaperone, SA4503, up-regulates BDNF protein levels in the rat hippocampus

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Numerous studies have shown the sigma-1 receptor chaperone (previously designated as the sigma-1 receptor) to play an important role in various neuronal functions, and selective ligands for sigma-1 receptor chaperone have been found to have therapeutic potential in certain psychiatric disorders and some forms of neuronal damage. Brain-derived neurotrophic factor (BDNF) is postulated to be related to the pharmacological action of sigma ligands, though the functional interaction between sigma-1 receptor chaperone ligands and BDNF remains to be clarified. This study was undertaken to investigate whether or not administration of SA4503, a selective ligand for sigma-1 receptor chaperone, affects BDNF levels in several regions of the rat brain. Rats were injected with SA4503 (0.3, 1 and 3 mg/(kg day), i.p.) once or repeatedly for 2 or 4 weeks. BDNF protein levels were estimated by Western blot analysis in the striatum, midbrain, frontal cortex, hippocampus and thalamus. A single injection of SA4503 did not change BDNF protein levels, while chronic injection for 2 or 4 weeks tended to increase BDNF levels in the hippocampus. In particular, 1 mg/kg of SA4503 daily for 2 weeks led to a statistically significant, i.e. twofold, increase in the BDNF protein level in the hippocampus. On the other hand, the TrkB receptor, a primary receptor for BDNF, exists in truncated and full-length isoforms, hippocampal levels of which were unaffected by SA4503 treatments. Our findings indicate that chronic administration of SA4503 may regulate region-specific BDNF functions in the rat brain.