Abstract
Purmorphamine (PUR), an agonist of the Smoothened (Smo) receptor, has been shown to function as a neuroprotectant in acute experimental ischemic stroke. Its role in hypoxic-ischemic (HI) brain injury in neonatal mice remains unknown. Here we show that PUR attenuated acute brain injury, with a decrease in Bax/Bcl-2 ratio as well as inhibition of caspase-3 activation. These beneficial effects of PUR were associated with suppressing neuro-inflammation and oxidative stress. PUR exerted long-term protective effects upon tissue loss and improved neurobehavioral outcomes as determined at 14 and 28 days post-HI insult. Moreover, PUR increased synaptophysin (Syn) and postsynaptic density (PSD) protein 95 expression in HI-treated mice and attenuated synaptic loss. PUR upregulated the expression of Shh pathway mediators, while suppression of the Shh signaling pathway with cyclopamine (Cyc) reversed these beneficial effects of PUR on HI insult. Our study suggests a therapeutic potential for short-term PUR administration in HI-induced injury as a result of its capacity to exert multiple protective actions upon acute brain injury, long-term memory deficits, and impaired synapses. Moreover, we provide evidence indicating that one of the mechanisms underlying these beneficial effects of PUR involves activation of the Shh signaling pathway.
Highlights
Perinatal brain injury due to HI is a serious health problem affecting full-term and preterm human neonate and is a contributor to perinatal morbidity and mortality (Volpe, 2012)
We examined the influences of a short-term PUR administration on acute brain injury and long-term neurobehavioral dysfunction in neonatal mice subjected to HI injury
We established that the 10 mg/kg dose exerted remarkable beneficial effects in the absence of any toxicity and we chose this dose for the subsequent experimental studies
Summary
Perinatal brain injury due to HI is a serious health problem affecting full-term and preterm human neonate and is a contributor to perinatal morbidity and mortality (Volpe, 2012). A number of beneficial effects result from Shh signaling as demonstrated in various pathological states of brain and spinal cord pathology, including acute brain injury (Amankulor et al, 2009), Alzheimer’s disease (Vazin et al, 2014), Parkinson’s disease (Tsuboi and Shults, 2002), stroke (Yu et al, 2017), multiple sclerosis and demyelination (Franco et al, 2008), spinal cord injury (Bambakidis et al, 2010), and HIV-associated neurological disorders (Singh et al, 2016). Exogenous Shh protein administration exerts angiogenic effects and protects against brain injury from ischemia (Chen et al, 2017)
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