CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery

•CRHR1 blockade impacts BDNF/TrkB protein and mRNA signaling.•Antalarmin normalizes responsiveness of the HPA axis post ischemia.•CRHR1 blockade reduces neuronal inflammation and CA1 and CA3 injury in ischemic rats.•Antalarmin improves post ischemic memory and emotional impairments.•CRHR1 activation of plasticity signals is involved in ischemic recovery.

This study examined the impact of corticotropin-releasing hormone type 1 receptor (CRHR1) blockade using Antalarmin (ANT) on the expression of markers of neuroplasticity and inflammation, as well as neuroprotection and behavioral recovery following global cerebral ischemia. Male Wistar rats (N = 50) were treated with ANT (2 μg/2 μl; icv) or a vehicle solution prior to a sham or four vessel (4VO) occlusion. Seven days post ischemia, anxiety was assessed in the Elevated Plus Maze and Open Field tests, and fear and spatial learning in a Y-Maze Passive Avoidance Task and the Barnes Maze. Thirty days post ischemia, brain derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor expression, hippocampal neuronal death and inflammation were determined by analyzing immunoreactivity (ir) of neuron-specific nuclear protein (NeuN), microglia (IBA1, ionized calcium binding adaptor molecule 1), astrocytes (GFAP, glial fibrillary acidic protein) and TNFα (tumor necrosis factor alpha) a pro-inflammatory cytokine. Our findings revealed that ANT improved behavioral impairments, while conferring neuroprotection and blunting neuroinflammation in all hippocampal sub-regions post ischemia. We also observed reduced BDNF and TrkB mRNA and protein levels at the hippocampus, and increased expression at the hypothalamus and amygdala post ischemia, site-specific alterations which were regularized by pre-ischemic CRHR1 blockade. These findings support that CRHR1 actively contributes to altered brain plasticity, neuronal inflammation and injury and recovery of function following ischemic brain insults.