Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia
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Published on: February 19, 2022
S Sundararajan1, J L Gamboa, N A Victor
1Department of Neurology, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Ave, Cleveland, OH 44106, USA. sophia.sundararajan@case.edu
Abstract:
Newly developed insulin-sensitizing agents, which target the nuclear receptor peroxisome proliferator-activated receptor-gamma have recently been appreciated to exhibit potent anti-inflammatory actions. Since stroke is associated with an intense inflammatory response, we reasoned that these agents may ameliorate injury from stroke. We report that administration of troglitazone or pioglitazone 24 h before and at the time of cerebral infarction dramatically reduced infarction volume and improved neurological function following middle cerebral artery occlusion in rats. Furthermore, we find that delayed therapy also significantly reduced infarct volume. The brains of the drug-treated animals displayed reduced inflammation as evidenced by decreased immunoreactivity for microglial/macrophage markers and reduced protein and mRNA for interleukin-1beta, cyclooxygenase-2 and inducible nitric oxide synthase. We argue that the beneficial effects of these drugs are likely due to reduced expression of these inflammatory mediators, which are known to exacerbate ischemic injury following stroke. These results are of particular relevance to diabetic patients chronically treated with these agents who may benefit from the neuroprotective actions of these drugs.
Insights
New stroke therapies show promise. Insulin-sensitizing drugs, like troglitazone and pioglitazone, reduce brain damage and inflammation after stroke by targeting PPAR-gamma, offering potential neuroprotection.
Area of Science:
- Neuroscience
- Pharmacology
- Inflammation Research
Background:
- Stroke triggers a significant inflammatory response, exacerbating brain injury.
- Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists possess anti-inflammatory properties.
- PPAR-gamma agonists are used as insulin-sensitizing agents.
Purpose of the Study:
- To investigate the neuroprotective effects of PPAR-gamma agonists in a rat model of ischemic stroke.
- To determine if troglitazone and pioglitazone can reduce brain infarction and improve neurological function post-stroke.
- To explore the impact of these agents on neuroinflammation markers.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in rats to induce ischemic stroke.
- Administration of troglitazone or pioglitazone before and at the time of MCAO, as well as delayed treatment.
- Assessment of infarct volume, neurological deficits, and brain inflammation markers (microglial/macrophage markers, IL-1beta, COX-2, iNOS).
Main Results:
- Troglitazone and pioglitazone significantly reduced infarct volume and improved neurological function when administered before or at the time of stroke.
- Delayed administration of these drugs also led to a significant reduction in infarct volume.
- Drug treatment decreased markers of inflammation in the brain, including microglial/macrophage activity and levels of IL-1beta, COX-2, and iNOS.
Conclusions:
- PPAR-gamma agonists, troglitazone and pioglitazone, demonstrate significant neuroprotective effects in ischemic stroke.
- The anti-inflammatory actions of these drugs contribute to the reduction of ischemic brain injury.
- These findings suggest potential therapeutic benefits for diabetic patients receiving these agents for stroke prevention or treatment.
