Nateglinide Exerts Neuroprotective Effects via Downregulation of HIF-1α/TIM-3 Inflammatory Pathway and Promotion of Caveolin-1 Expression in the Rat’s Hippocampus Subjected to Focal Cerebral Ischemia/Reperfusion Injury

• Published in: Inflammation 2020-04, Vol.43 (2), p.401-416
• Main Authors: Saad, Muhammad Abd El-Latif, Fahmy, Mohamed Ibrahim Mohamed, Al-Shorbagy, Muhammad, Assaf, Naglaa, Hegazy, Ahmed Abd El-Aziz, El-Yamany, Muhammad Farag
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers; Biomedical and Life Sciences; Biomedicine; Brain Ischemia - metabolism; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Caspase-3; Caveolin; Caveolin 1 - biosynthesis; Caveolin-1; Cerebral blood flow; Diabetes mellitus (non-insulin dependent); Down-Regulation - drug effects; Down-Regulation - physiology; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Internal Medicine; Ischemia; Janus kinase; Janus kinase 2; Male; Nateglinide - pharmacology; Nateglinide - therapeutic use; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NF-κB protein; Nitric oxide; Original Article; Pathology; Peroxidase; Pharmacology/Toxicology; Psychomotor Performance - drug effects; Psychomotor Performance - physiology; Rats; Rats, Wistar; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism; Reperfusion; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; Rheumatology; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Stat3 protein; Stroke; Transcription; Tumor necrosis factor; Tumor necrosis factor-TNF
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-019-01154-3

Ischemic stroke is a major cause of death and motor disabilities all over the world. It is a muti-factorial disorder associated with inflammatory, apoptotic, and oxidative responses. Nateglinide (NAT), an insulinotropic agent used for the treatment of type 2 diabetes mellitus, recently showed potential anti-inflammatory and anti-apoptotic effects. The aim of our study was to elucidate the unique neuroprotective role of NAT in the middle cerebral artery occlusion (MCAO)-induced stroke in rats. Fifty-six male rats were divided to 4 groups ( n  = 14 in each group): the sham-operated group, sham receiving NAT (50 mg/kg/day, p.o) group, ischemia/reperfusion (IR) group, and IR receiving NAT group (50 mg/kg/day, p.o). MCAO caused potent deficits in motor and behavioral functions of the rats. Significant increase in inflammatory and apoptotic biomarkers has been observed in rats’ hippocampi. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was significantly stimulated causing activation of series inflammatory biomarkers ending up neuro-inflammatory milieu. Pretreatment with NAT preserved rats’ normal behavioral and motor functions. Moreover, NAT opposed the expression of hypoxia-inducible factor-1α (HIF-1α) resulting in downregulation of more inflammatory mediators namely, NF-κB, tumor necrosis factor-β (TNF-β), and the anti-survival gene PMAIP-1. NAT stimulated caveolin-1 (Cav-1) which prevented expression of oxidative biomarkers, nitric oxide (NO), and myeloperoxidase (MPO) and hamper the activation of apoptotic biomarker caspase-3. In conclusion, our work postulated that NAT exhibited its neuroprotective effects in rats with ischemic stroke via attenuation of different unique oxidative, apoptotic, and inflammatory pathways.