Neuroprotective Effects of a Smoothened Receptor Agonist against Early Brain Injury after Experimental Subarachnoid Hemorrhage in Rats

Abstract

The sonic hedgehog (Shh) signaling pathway plays a fundamental role in the central nervous system (CNS) development, but its effects on neural cell survival and brain repair after subarachnoid hemorrhage (SAH) has not been well-investigated. The present study was undertaken to evaluate the influence of an agonist of the Shh co-receptor Smoothened (Smo), purmorphamine (PUR), on early brain injury (EBI) as well as the underlying mechanisms after SAH. PUR was administered via an intraperitoneal injection with a dose of 0.5, 1, and 5 mg/kg at 2, 6, 24, and 46 h after SAH in rat model. The results showed that PUR treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the prefrontal cortex (PFC), associated with a decrease in Bax/Bcl-2 ratio and suppression of caspase-3 activation at 48 h after SAH. PUR also promoted phospho-ERK levels. Additionally, PUR treatment markedly decreased MDA concentration accompanied with the elevation in the expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in PFC. Notably, PUR treatment significantly reversed the changes of Shh pathway mediators containing Patched, Gli1, and Shh by SAH insult, and the neuroprotection of PUR on SAH was blocked by Smo antagonist cyclopamine. These results indicated that PUR exerts neuroprotection against SAH-evoked injury in rats, mediated in part by anti-apoptotic and anti-oxidant mechanism, up-regulating phospho-ERK levels, mediating Shh signaling molecules in the PFC.

Purmorphamine Attenuates Neuro-Inflammation and Synaptic Impairments After Hypoxic-Ischemic Injury in Neonatal Mice via Shh Signaling

“…Taken together, blocking microglial activation may contribute to the neuroprotective effects of PUR in immature brain in mice following HI. The capacity for PUR to exert antioxidant effects in HI, as revealed by significantly decreasing HI-induced ROS levels, was consistent with a previous study (Hu et al, 2016). A number of antioxidants, including allopurinol, erythropoietin, resveratrol, and omega-3 fatty acids, have been shown to exhibit neuroprotective properties in different animal models of perinatal HI brain injury (Peeters-Scholte et al, 2003;Arteaga et al, 2017;Revuelta et al, 2017).…”

“…In addition, the endogenous Shh pathway in the cortex and hippocampus was reported to be upregulated in response to stroke and ischemic insult (Sims et al, 2009;Chechneva et al, 2014). However, Shh expression in the cortex was downregulated in the early stages after experimental subarachnoid hemorrhage (Zuo et al, 2015;Hu et al, 2016). In the present study, the expression of Shh signaling including Shh and Ptch within brain was reduced following HI insult.…”

“…Recently, PUR was found to participate in neuroprotective effects against ischemic injury, which were reported to be independent of the Shh signaling pathway (Chechneva et al, 2014). Previous work within our laboratory has indicated that PUR provided neuroprotection against subarachnoid hemorrhage-induced injury (Hu et al, 2016). However, only limited information currently exists in support of PUR neuroprotection and its mechanisms, which may involve antiinflammatory, anti-apoptotic, and/or pro-angiogenic processes after ischemic insult (Chechneva et al, 2014;Chechneva and Deng, 2015).…”

“…Recently, PUR was found to protect cortical neurons and restore neurological deficits after ischemic stroke in rats (Chechneva et al, 2014). Work within our laboratory has revealed that PUR exerts neuroprotection against subarachnoid hemorrhage-induced injury in rats (Hu et al, 2016). To the best of our knowledge, the potential effects of PUR within neonatal animals subjected to HI injury remain unknown.…”

Neuroprotective Effects of the Sonic Hedgehog Signaling Pathway in Ischemic Injury through Promotion of Synaptic and Neuronal Health

“…PUR, which has also been shown to promote blood-brain barrier formation, plays a crucial role in activation of the endogenous anti-inflammatory system within the CNS [ 9 ], and recent findings have indicated that PUR protects cortical neurons and restores neurological deficits after ischemic stroke in rats [ 10 ]. It has been reported by us that PUR exerted neuroprotection against subarachnoid hemorrhage-induced injury in adult rats [ 11 ] and hypoxia-ischemia in neonatal mice [ 12 ].…”