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Addressing Peroxisome Proliferator-Activated Receptor-gamma in 3-Nitropropionic Acid-Induced Striatal Neurotoxicity
Riham M Mansour1, Nesrine S El Sayed2, Maha A E Ahmed3
1Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology (MUST), 6Th of October City, Giza, Egypt. reham.mansour@must.edu.eg.
Abstract:
Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and a partial activator of peroxisome proliferator-activated receptor-gamma (PPARγ), which regulates inflammatory and apoptotic pathways. Increasing evidence has demonstrated the PPARγ agonistic property of TEL in several brain disorders. This study aims to explore the neuroprotective impact of TEL in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. The PPARγ effect of TEL was affirmed by using the PPARγ agonist pioglitazone (PIO), and the antagonist GW9662. 3-NP led to a significant reduction in body weight alongside motor and cognitive functioning. The striata of the 3-NP-treated rats showed energy-deficit, microglia-mediated inflammatory reactions, apoptotic damage as well as histopathological lesions. PIO and TEL improved motor and cognitive perturbations induced by 3-NP, as confirmed by striatal histopathological examination, energy restoration, and neuronal preservation. Both drugs improved mitochondrial biogenesis evidenced by elevated mRNA expression of PPARγ, PGC-1α, and TFAM, alongside increased striatal ATP and SDH. The mitochondrial effect of TEL was beyond PPARγ activation. As well, their anti-inflammatory effect was attributed to suppression of microglial activation, and protein expression of pS536 p65 NF-κB with marked attenuation of striatal inflammatory mediator's release. Anti-inflammatory cytokine IL-10 expression was concurrently increased. TEL effectively participated in neuronal survival as it promoted phosphorylation of Akt/GSK-3β, further increased Bcl-2 expression, and inhibited cleavage of caspase-3. Interestingly, co-treatment with GW9662 partially revoked the beneficial effects of TEL. These findings recommend that TEL improves motor and cognitive performance, while reducing neuronal inflammation and apoptosis in 3-NP-induced neurotoxicity via a PPARγ-dependent mechanism.
Insights
Telmisartan (TEL) protects against 3-nitropropionic acid (3-NP)-induced neurotoxicity by improving motor and cognitive functions. It reduces neuroinflammation and apoptosis, primarily through peroxisome proliferator-activated receptor-gamma (PPARγ) activation.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Telmisartan (TEL) is an angiotensin II receptor blocker with peroxisome proliferator-activated receptor-gamma (PPARγ) agonistic properties.
- PPARγ activation influences inflammatory and apoptotic pathways relevant to brain disorders.
- 3-nitropropionic acid (3-NP) is used to induce neurotoxicity, modeling energy deficits and motor/cognitive impairments.
Purpose of the Study:
- To investigate the neuroprotective effects of Telmisartan (TEL) in a rat model of 3-nitropropionic acid (3-NP)-induced neurotoxicity.
- To elucidate the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in mediating TEL's neuroprotective actions.
- To assess TEL's impact on mitochondrial function, inflammation, and apoptosis in the striatum.
Main Methods:
- Induction of neurotoxicity in rats using 3-nitropropionic acid (3-NP).
- Administration of Telmisartan (TEL), pioglitazone (PIO, PPARγ agonist), and GW9662 (PPARγ antagonist).
- Assessment of motor and cognitive functions, striatal histopathology, energy metabolism (ATP, SDH), mitochondrial biogenesis markers (PPARγ, PGC-1α, TFAM), inflammatory markers (microglia, NF-κB, inflammatory mediators), and apoptosis markers (Bcl-2, caspase-3).
Main Results:
- 3-NP induced significant motor/cognitive deficits, energy deficit, inflammation, and apoptosis in rat striata.
- TEL and PIO treatment ameliorated 3-NP-induced neurotoxicity, restoring motor/cognitive functions and neuronal integrity.
- TEL enhanced mitochondrial biogenesis, suppressed microglial activation and inflammation, and promoted neuronal survival pathways.
- The PPARγ antagonist GW9662 partially reversed the beneficial effects of TEL, confirming a PPARγ-dependent mechanism.
Conclusions:
- Telmisartan (TEL) demonstrates significant neuroprotective effects against 3-NP-induced neurotoxicity in rats.
- TEL's benefits are mediated through PPARγ-dependent mechanisms, including improved mitochondrial function, reduced inflammation, and inhibition of apoptosis.
- These findings highlight TEL's therapeutic potential for neurodegenerative conditions characterized by energy deficits and inflammation.
