Citation: Foudah, A.I.; Devi, S.; Alqarni, M.H.; Alam, A.; Salkini, M.A.; Kumar, M.; Almalki, H.S. Quercetin Attenuates Nitroglycerin-Induced Migraine Headaches by Inhibiting Oxidative Stress and Inflammatory Mediators. Nutrients 2022, 14, 4871. https:// doi.org/10.3390/nu14224871 Academic Editors: Abdelouahed Khalil, Sonya Vasto and Maria Luz Fernandez Received: 6 October 2022 Accepted: 15 November 2022 Published: 17 November 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Article Quercetin Attenuates Nitroglycerin-Induced Migraine Headaches by Inhibiting Oxidative Stress and Inflammatory Mediators Ahmed I. Foudah 1, * , Sushma Devi 2 , Mohammed H. Alqarni 1 , Aftab Alam 1, * , Mohammad Ayman Salkini 1 , Manish Kumar 2,3 and Husam Saad Almalki 1 1 Departmentof Pharmacognosy, College of Pharmacy, Prince SattamBin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia 2 Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, India 3 Department of Neurosurgery, College of Medicine, Penn State Health Milton S. Hershey Medical Center, The Pennsylvania State University, State College, PA 17033-0850, USA * Correspondence: a.foudah@psau.edu.sa (A.I.F.); a.alam@psau.edu.sa (A.A.) Abstract: This study aimed to investigate the antimigraine potential of quercetin in migraine pain induced by nitroglycerin (NTG), 10 mg/kg, intraperitoneal injection in rats. Quercetin was administered orally for 1 week, and behavioral parameters associated with pain were assessed 30 min after NTG injection. At the end of the study, the rats were killed so that immunohistochemical examination of their brains could be performed. The time and frequency of rearing and sniffing in the category of exploratory behavior, walking in the category of locomotor behavior, and total time spent in the light chamber were reduced in the disease control group compared with the normal group during the assessment of behavioral parameters. Pathologic migraine criteria, such as increased levels of calcitonin gene-related peptide and increased release of c-fos cells, were more prominent in the caudal nucleus triceminalis of the NTG control group. In the treatment groups, behavioral and pathological measures were less severe after pretreatment with quercetin at doses of 250 and 500 mg/kg. Therefore, it was concluded that quercetin improved the pain behavior of migraine patients in the NTG-induced migraine rat model. Quercetin is thought to have antimigraine effects due to its antioxidant and anti-inflammatory potential. Quercetin may therefore be a novel agent that can treat or prevent migraine pain and associated avoidance behaviors. Keywords: migraine; quercetin; locomotor behavior; nitroglycerine; antimigraine 1. Introduction Most often, any type of pain is due to inflammation or nerve damage. Migraine is a recurrent neurological pain disorder that affects the health, social, and economic situation of patients. According to epidemiological reports, migraine affects 1 in 10 people worldwide, and its incidence continues to increase inconspicuously [1]. In the Global Burden of Diseases 2016, migraine was reported to be the sixth most common disease among 328 diseases and harms. In addition, migraine was ranked as the second most common disease in which life is lived with disability [2]. Migraine is defined according to the International Classification of Headache Disorders as a “recurrent headache disorder manifested in attacks lasting 4–72 h.” Migraine is characterized by moderate to severe throbbing or pulsating pain. The pain may be unilateral, may have a pulsatile quality, and may interfere with physical activity. In addition to the typical features, other symptoms may include nausea, fatigue, photophobia, or phonophobia [3]. All over the world, pain treatment with classical drugs (NSAIDs) is a challenge. This is because such treatments are associated with many side effects and are iatrogenic. In clinical trials, these NSAIDs showed numerous side effects and led to an increase in Nutrients 2022, 14, 4871. https://doi.org/10.3390/nu14224871 https://www.mdpi.com/journal/nutrients