Carnosine Protects against Cerebral Ischemic Injury by Inhibiting Matrix-Metalloproteinases.

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Ischemic stroke is a major cause of death and disability globally, with limited therapeutic options.
• Matrix-metalloproteinases (MMPs) exacerbate ischemic stroke damage by compromising the blood-brain barrier (BBB) and causing brain edema.
• Carnosine, an endogenous dipeptide, has demonstrated potential neuroprotective properties against ischemic brain injury.

Purpose of the Study:

• To investigate the effect of carnosine on matrix-metalloproteinase (MMP) activity in the context of ischemic stroke.
• To elucidate the mechanism by which carnosine exerts its neuroprotective effects against ischemic brain damage.

Main Methods:

• Permanent occlusion of the middle cerebral artery (pMCAO) in rats was used to induce ischemic stroke.
• Brain MMP levels and activity were assessed using gelatin zymography.
• In vitro enzyme assays were conducted to determine carnosine's direct effect on MMPs and its mechanism of action.

Main Results:

• Carnosine administration significantly reduced infarct volume and cerebral edema in a rat model of ischemic stroke.
• Both gelatin zymography and in vitro assays demonstrated that carnosine inhibits the activity of brain MMPs, specifically MMP-2 and MMP-9.
• Carnosine was found to inhibit MMP activity by chelating zinc, an essential cofactor for MMPs, and reduced ischemia-induced degradation of tight junction proteins in the BBB.

Conclusions:

• Carnosine exhibits neuroprotective effects against ischemic stroke by inhibiting MMP activity through zinc chelation.
• This mechanism reduces cerebral edema and brain injury by preserving the integrity of the blood-brain barrier.
• Carnosine represents a promising therapeutic agent for mitigating ischemic brain damage, offering a novel neuroprotective strategy.