A Smoothened receptor agonist is neuroprotective and promotes regeneration after ischemic brain injury

作者：Chechneva, O. V.; Mayrhofer, F.; Daugherty, D. J.; Krishnamurty, R. G.; Bannerman, P.; Pleasure, D. E.; Deng, W.^*

来源：Cell Death & Disease, 2014, 5(10): e1481.

DOI：10.1038/cddis.2014.446

• TISSUE-PLASMINOGEN ACTIVATOR
• FOCAL CEREBRAL-ISCHEMIA
• SONIC HEDGEHOG
• NEURONAL DEGENERATION
• DOPAMINERGIC-NEURONS
• REACTIVE ASTROCYTES
• PATHWAY ACTIVATION
• CELL-PROLIFERATION
• BARRIER INTEGRITY
• EXPRESSION

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.

• 出版日期2014-10
• 单位湖北文理学院