Swati Chaturvedi1, Mohd Yaseen Malik1, Mamunur Rashid2, Sandeep Singh1, Virendra Tiwari3, Parul Gupta4, Shubha Shukla3, Sarika Singh4, Muhammad Wahajuddin5. 1. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research, New Delhi, India. 2. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, India. 3. Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research, New Delhi, India. 4. Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow, 226031, India. 5. Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, 226031, India. Electronic address: wahajuddin@cdri.res.in.
Abstract
AIM: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin. MAIN METHODS: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl2, iNOS, eNOS and caspase-3. KEY FINDINGS: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl2 and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers. SIGNIFICANCE: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole.
AIM: Metronidazole, a nitroimidazole derived antibiotic used to treat many bacterial infections, is reported to penetrate the blood brain barrier after long term administration resulting into neuronal toxicity. Further, quercetin, a polyphenol flavonoid is reported to exhibit neuroprotective activity but its pharmacodynamics interaction against metronidazole induced neurotoxicity. Therefore, the present study was designed to evaluate the postulated mechanism of metronidazole induced neurotoxicity and potential neuroprotective role of quercetin. MAIN METHODS: Animals (Sprague Dawley) rats were randomly divided into five groups such as control, metronidazole (135 mg/kg), quercetin (100 mg/kg), metronidazole (135 mg/kg) + quercetin (50 mg/kg), and metronidazole (135 mg/kg) + quercetin (100 mg/kg). The brain tissues were evaluated for tissue cyclo-oxygenase, lipoxygenase, nitrite levels, inflammatory and antioxidant biomarkers. The brain tissues were further scrutinized histopathologically for neuronal degeneration. Western blotting analysis was performed for the localization of protein expression for Bax, Bcl2, iNOS, eNOS and caspase-3. KEY FINDINGS: The metronidazole significantly alters the antioxidant levels, inflammatory mediators and morphological changes in the brain tissue. Metronidazole also induces iNOS, Bax and caspase 3 protein expressions whilst decreases the expression of Bcl2 and eNOS in the brain tissue. Metronidazole administration causes a momentous increase in tissue inflammatory markers. SIGNIFICANCE: The metronidazole (oral) administration causes remarkably neurotoxicity effects and the same could be attributed to the fact that metronidazole has the ability to cross the blood brain barrier and transforms the enzymatic activity of various biomarkers present in the brain. From the results, it could be hypothesized that metronidazole causes neurotoxicity by hindering the proportion of antioxidants in the brain tissue and inducing nitric oxide synthesis along with apoptosis. However, quercetin demonstrated a significant protective effect on neuronal toxicity precipitated through metronidazole.
Authors: Samar S Elblehi; Eman M Abd El-Maksoud; Adil Aldhahrani; Saqer S Alotaibi; Heba I Ghamry; Salwa A Elgendy; Mohamed Mohamed Soliman; Mustafa Shukry Journal: Life (Basel) Date: 2022-04-13