Trigonelline therapy confers neuroprotection by reduced glutathione mediated myeloperoxidase expression in animal model of ischemic stroke

• Published in: Life sciences (1973) 2019-01, Vol.216, p.49-58
• Main Authors: Pravalika, Kanta, Sarmah, Deepaneeta, Kaur, Harpreet, Vats, Kanchan, Saraf, Jackson, Wanve, Madhuri, Kalia, Kiran, Borah, Anupom, Yavagal, Dileep R., Dave, Kunjan R., Bhattacharya, Pallab
• Format: Article
• Language: English
• Subjects: Alkaloids - administration & dosage; Alkaloids - pharmacology; Aniline Compounds - pharmacology; Animals; Antioxidants; Antioxidants - metabolism; Biochemical analysis; Biocompatibility; Blotting, Western; Brain; Brain Ischemia - drug therapy; Brain Ischemia - pathology; Cerebral blood flow; Cerebral infarction; Cerebral Infarction - drug therapy; Cerebral Infarction - pathology; Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Evaluation; Glutathione; Glutathione - metabolism; In vivo methods and tests; Inflammation; Inhibition; Ischemia; Ischemic stroke; Male; Myeloperoxidase; Neurodegenerative diseases; Neurological diseases; Neuroprotection; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacology; Occlusion; Peroxidase; Peroxidase - metabolism; Pharmacology; Rats; Rats, Sprague-Dawley; Reperfusion; Rodents; Stroke; Stroke - drug therapy; Stroke - pathology; Therapeutic applications; Toxicity; Trigonelline
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2018.11.014

Stroke is devastating with a limited choice of intervention. Many pharmacological entities are available but none of them have evolved successfully in counteracting the multifaceted molecular alterations following stroke. Myeloperoxidase (MPO) has been reported to play an important role in neuroinflammation following neurodegenerative diseases. Therefore, using it as a therapeutic target may be a strategy to confer neuroprotection in stroke. Trigonelline (TG), a plant alkaloid has shown neuroprotective effects in the past. Here we explore its neuroprotective effects and its role in glutathione mediated MPO inhibition in ischemic stroke. An in silico study was performed to confirm effective TG and MPO interaction. An in vitro evaluation of toxicity with biochemical estimations was performed. Further, in vivo studies were undertaken where rats were treated with 25, 50 and 100 mg/kg TG or standard MPO inhibiting drug4‑Aminobenzoic hydrazide (4‑ABH) at 60 min prior, post immediate and an hour post 90 min of middle cerebral artery occlusion (MCAo) followed by 24 h reperfusion. Rats were evaluated for neurodeficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, and western blot experiments. TG at 100 mg/kg dose i.p. administered immediately post ischemia confers neuroprotection by reducing cerebral infarct with improvement in motor and neurodeficit scores. Furthermore, elevated nitrite and MDA levels were also found to be reduced in brain regions in the treated group. TG also potentiated intrinsic antioxidant status and markedly inhibited reduced glutathione mediated myeloperoxidase expression in the cortical brain region. TG confers neuroprotection by reduced glutathione mediated myeloperoxidase inhibition in ischemic stroke.