Abstract
Ischemic stroke occurs as a result of blood supply interruption to the brain causing tissue degeneration, patient disabilities or death. Currently, treatment of ischemic stroke is limited to thrombolytic therapy with a narrow time window of administration. The sonic hedgehog (Shh) signaling pathway has a fundamental role in the central nervous system development, but its impact on neural cell survival and tissue regeneration/repair after ischemic stroke has not been well investigated. Here we report the neuroprotective properties of a small-molecule agonist of the Shh co-receptor Smoothened, purmorphamine (PUR), in the middle cerebral artery occlusion model of ischemic stroke. We found that intravenous administration of PUR at 6 h after injury was neuroprotective and restored neurological deficit after stroke. PUR promoted a transient upregulation of tissue-type plasminogen activator in injured neurons, which was associated with a reduction of apoptotic cell death in the ischemic cortex. We also observed a decrease in blood–brain barrier permeability after PUR treatment. At 14 d postinjury, attenuation of inflammation and reactive astrogliosis was found in PUR-treated animals. PUR increased the number of newly generated neurons in the peri-infarct and infarct area and promoted neovascularization in the ischemic zone. Notably, PUR treatment did not significantly alter the ischemia-induced level of Gli1, a Shh target gene of tumorigenic potential. Thus our study reports a novel pharmacological approach for postischemic treatment using a small-molecule Shh agonist, providing new insights into hedgehog signaling-mediated mechanisms of neuroprotection and regeneration after stroke.
Highlights
Approved treatment of stroke. type plasminogen activator (tPA) clinical use is limited to a narrow time window of safe administration and associated with dangers of intracranial hemorrhage.[1]
In the adult central nervous system (CNS), sonic hedgehog (Shh) is expressed in forebrain neurons and astrocytes, cerebellar Purkinje and motor neurons.[3]
Shh signaling is activated in response to CNS injury, and the time window and the cellular players involved is dependent on the type and severity of insult
Summary
Approved treatment of stroke. tPA clinical use is limited to a narrow time window of safe administration and associated with dangers of intracranial hemorrhage.[1]. Multiple studies showed the beneficial role of Shh signaling in various models of neurological conditions, including stroke,[10,13,14,15,16,17,18] acute brain injury,[19] Parkinson’s disease,[20,21] Alzheimer’s disease,[22] multiple sclerosis and demyelination,[11,23,24] spinal cord injury,[25,26] amyotrophic lateral sclerosis,[27] and glucocorticoid-induced cerebellar injury in neonates.[28] the potential of pharmacological activation of Shh signaling in injured CNS and associated neuroprotective mechanisms are unknown. We investigated the neuroprotective and regenerative properties of PUR in an experimental model of ischemic stroke
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