Neuroprotective effect of chronic lithium treatment against hypoxia in specific brain regions with upregulation of cAMP response element binding protein and brain-derived neurotrophic factor but not nerve growth factor: comparison with acute lithium treatment

Objectives: We evaluated the neuroprotective effect of chronically or acutely administered lithium against hypoxia in several brain regions. Furthermore, we investigated the contribution of brain‐derived neurotrophic factor (BDNF), nerve growth factor (NGF), and cAMP response element binding protein (CREB) to the neuroprotective effect of lithium. Methods: Brain slices were prepared from rats that had been treated chronically or acutely with lithium. The cerebral glucose metabolic rate (CMRglc) before and after hypoxia loading to brain slices was measured using the dynamic positron autoradiography technique with [18F]2‐fluoro‐2‐deoxy‐d‐glucose. The changes of expression of proteins were investigated using Western blot analysis. Results: Before hypoxia loading, the CMRglc did not differ between the lithium‐treated and untreated groups. After hypoxia loading, the CMRglc of the untreated group was significantly lower than that before hypoxia loading. However, the CMRglc of the chronic lithium treatment group recovered in the frontal cortex, caudate putamen, hippocampus and cerebellum, but not in the thalamus. In contrast, the CMRglc of the acute lithium treatment group did not recover in any analyzed brain regions. After chronic lithium treatment, the levels of expression of BDNF and phospho‐CREB were higher than those of untreated rats in the frontal cortex, but not in the thalamus. However, the expression of NGF did not change in the frontal cortex and thalamus. Conclusions: These results demonstrated that lithium was neuroprotective against hypoxia only after chronic treatment and only in specific brain regions, and that CREB and BDNF might contribute to this effect.