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

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.

• Authors: O V Chechneva, F Mayrhofer, D J Daugherty, R G Krishnamurty, P Bannerman, D E Pleasure, W Deng
• Journal: Cell death & disease (Cell Death Dis) Vol. 5 Pg. e1481 (Oct 23 2014) ISSN: 2041-4889 [Electronic] England
• PMID: 25341035 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hedgehog Proteins
• Morpholines
• Neuroprotective Agents
• Purines
• Receptors, G-Protein-Coupled
• Smo protein, mouse
• Smoothened Receptor
• Tissue Plasminogen Activator
• purmorphamine

Topics

• Animals
• Apoptosis (drug effects)
• Brain Ischemia (complications, drug therapy, pathology, physiopathology)
• Cerebral Cortex (drug effects, pathology, physiopathology)
• Disease Models, Animal
• Hedgehog Proteins (metabolism)
• Inflammation (pathology)
• Male
• Mice, Inbred C57BL
• Morpholines (pharmacology, therapeutic use)
• Nerve Regeneration (drug effects)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Purines (pharmacology, therapeutic use)
• Receptors, G-Protein-Coupled (agonists, metabolism)
• Signal Transduction (drug effects)
• Smoothened Receptor
• Stroke (complications, physiopathology)
• Time Factors
• Tissue Plasminogen Activator (metabolism)
• Up-Regulation (drug effects)