Guanfacine promotes neuronal survival in medial prefrontal cortex under hypobaric hypoxia

Abstract High altitude hypobaric hypoxia (HH) affects prefrontal cognitive and executive functions. Guanfacine, alpha 2A adrenoceptor agonist ameliorates the neurological outcomes of high altitude exposure and associated prefrontal neurodegeneration. However, the molecular mechanism underlying the neuroprotective effect of guanfacinefollowing HH remains elusive. Altered balance of pro and anti-apoptotic proteins have been implicated in the beneficial effect of guanfacineto enhance neuronal survival. We examined the effects of guanfacineon expression of some key neurotropicand cytoskeletal proteins following HH. Male rats were exposed to simulated altitude of 7620 m and received an intramuscular injection of either saline or guanfacineat a dose of 1 mg/kg for 7 consecutive days. Differential expression of desired proteins was evaluated in layer II of medial prefrontal cortex (PFC) by biochemical and immunohistochemical assays. Guanfacinetreatment significantly increased the expression of BDNF in layer II of the medial PFC during normoxia and HH. Moreover, there was a negative correlation of this neurotropicfactor with neurodegenerationof pyramidal cellspresent in this layer of medial PFC. We found a significant decrease in Caspase3 and Bax while a significant increase in Bcl2 with guanfacinetreatment during HH. Further, change in Bax to Bcl2 ratio was in correlation with Caspase3 expression in layer II of the medial PFC, indicating that Caspase3 is responsible for Bcl2 cleavage and hence modulation of apoptosis. Guanfacinetreatment induced a marked and significant increase in MAP2 and Spinophilin expression in dendritic arbors and spines respectively. Interestingly, alteration in these cytoskeletal proteins was accompanied by simultaneous changes in morphological parameters of dendrites in layer II of medial PFC. Guanfacinemodulates the neurotropic, cytoskeletal, pro and anti-apoptotic protein expression in medial PFC under HH and therefore serve as a countermeasure in the amelioration of HH induced alteration in these proteins.