Abstract
Ketamine exposure can model cognitive deficits associated with schizophrenia. Progesterone (PROG) and its active metabolite allopregnanolone (ALLO) have neuroprotective effects and the pathway involving progesterone receptor membrane component 1 (PGRMC1), epidermal growth factor receptor (EGFR), glucagon-like peptide-1 receptor (GLP-1R), phosphatidylinositol 3 kinase (PI3K), and protein kinase B (Akt) appears to play a key role in their neuroprotection. The present study aimed to investigate the effects of PROG (8,16 mg kg−1) and ALLO (8,16 mg kg−1) on the reversal of cognitive deficits induced by ketamine (30 mg kg−1) via the PGRMC1 pathway in rat brains, including hippocampus and prefrontal cortex (PFC). Cognitive performance was evaluated by Morris water maze (MWM) test. Western blot and real-time quantitative polymerase chain reaction were utilized to assess the expression changes of protein and mRNA. Additionally, concentrations of PROG and ALLO in plasma, hippocampus and PFC were measured by a liquid chromatography-tandem mass spectrometry method. We demonstrated that PROG or ALLO could reverse the impaired spatial learning and memory abilities induced by ketamine, accompanied with the upregulation of PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway. Additionally, the coadministration of AG205 abolished their neuroprotective effects and induced cognitive deficits similar with ketamine. More importantly, PROG concentrations were markedly elevated in PROG-treated groups in hippocampus, PFC and plasma, so as for ALLO concentrations in ALLO-treated groups. Interestingly, ALLO (16 mg kg−1) significantly increased the levels of PROG. These findings suggest that PROG can exert its neuroprotective effects via activating the PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway in the brain, whereas ALLO also restores cognitive deficits partially via increasing the level of PROG in the brain to activate the PGRMC1 pathway.
Highlights
Cognitive deficits have been recognized as a core feature of firstepisode and drug-naive schizophrenia patients (Aas et al, 2014; Chu et al, 2019)
The prevailing view holds that PROG exerts its neuroprotective effects through multiple receptors: classical progesterone receptors (Pgr), progesterone receptor membrane component 1 (PGRMC1), membrane progesterone receptors, and GABAA receptors after conversion to ALLO (Cooke et al, 2013; Guennoun et al, 2015)
Based on the fact that the level of Akt is significantly decreased in schizophrenia (Zheng et al, 2012), our present study revealed the downregulation of the phosphatidylinositol 3 kinase (PI3K)/Akt pathway in sub-chronic ketamine-exposed rats with cognitive impairment
Summary
Cognitive deficits have been recognized as a core feature of firstepisode and drug-naive schizophrenia patients (Aas et al, 2014; Chu et al, 2019). Cognitive deficits can strongly predict long-term functional disability in schizophrenia patients, but current antipsychotic treatments lack efficacy for improving cognition in patients (Hill et al, 2010). It has been demonstrated that the neurosteroids progesterone (PROG) and allopregnanolone (ALLO) exert several functional effects in the brain, such as neuroprotection against some nervous system diseases, including traumatic brain injury (TBI) (Si et al, 2013) and spinal cord injury (Cooke et al, 2013) and schizophrenia-related cognitive dysfunction (Cai et al, 2018a). The prevailing view holds that PROG exerts its neuroprotective effects through multiple receptors: classical progesterone receptors (Pgr), PGRMC1, membrane progesterone receptors (mPR), and GABAA receptors after conversion to ALLO (Cooke et al, 2013; Guennoun et al, 2015)
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