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Efficacy of Melatonin in Animal Models of Subarachnoid Hemorrhage: A Systematic Review and Stratified Meta-Analysis
Xiangyu Hu
Yuwei Zhu†, 
Fangfang Zhou
Zhiping Hu- Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China
Background and Purpose: Subarachnoid hemorrhage (SAH) is a severe disease characterized by sudden headache, loss of consciousness, or focal neurological deficits. Melatonin has been reported as a potential neuroprotective agent of SAH. It provides protective effects through the anti-inflammatory effects or the autophagy pathway. Our systematic review aims to evaluate the efficacy of melatonin administration on experimental SAH animals and offer support for the future clinical trial design of the melatonin treatment following SAH.
Methods: The following online databases were searched for experimentally controlled studies of the effect of melatonin on SAH models: PubMed, Web of Knowledge, Embase, and China National Knowledge Infrastructure (all until March 2021). The melatonin effect on the brain water content (BWC) and neurological score (NS) were compared between the treatment and control groups using the standardized mean difference (SMD).
Results: Our literature identified 160 possible articles, and most of them were excluded due to duplication (n = 69) and failure to meet the inclusion criteria (n = 56). After screening the remaining 35 articles in detail, we excluded half of them because of no relevant outcome measures (n = 16), no relevant interventions (n = 3), review articles (n = 1), duplicated publications (n = 1), and studies on humans or cells (n = 2). Finally, this systematic review contained 12 studies between 2008 and 2018. All studies were written in English except for one study in Chinese, and all of them showed the effect of melatonin on BWC and NS in SAH models.
Conclusion: Our research shows that melatonin can significantly improve the behavior and pathological results of SAH animal models. However, due to the small number of studies included in this meta-analysis, the experimental design and experimental method limitations should be considered when interpreting the results. Significant clinical and animal studies are still required to evaluate whether melatonin can be used in the adjuvant treatment of clinical SAH patients.
Introduction
Although it only leads to 4.4% of all types of strokes, subarachnoid hemorrhage (SAH) is a severe disease with high mortality and morbidity (1). SAH is characterized by clinical features such as sudden headache, single or combined with vomiting, loss of consciousness, or focal neurological deficits (2). At present, the management and prevention of SAH are still challenging due to its intricate pathophysiological conditions (3). Rupture of intracranial aneurysms is a typical cause of SAH (4). Zero to 24 h after hemorrhage, early brain injury (EBI) is observed in focal (5), together with blood–brain barrier damage and vascular spasms (6). Further cellular changes include inflammation and autophagy. The released products mediate and persist inflammatory responses by danger-associated molecular patterns (DAMPs) (7). Activation of the MAPK (mitogen-activated protein kinase) and Keap1-Nrf2-ARE [(Kelch-like ECH-Associating protein 1) nuclear factor erythroid 2 related factor 2-antioxidant response element] pathways may take over part of the inflammatory damage mechanism (8, 9). The EBI following SAH can also be induced by the autophagy mechanism (10), with the activation of mitochondria and the downstream pathway (11).
Recently, melatonin (N-acetyl-5-methoxytryptamine) has been reported as a potential neuroprotective agent of SAH. Melatonin, which derives from tryptophan (12), was demonstrated to counterwork oxidative stress and assist in scavenging free radicals (13). In 2010, researchers raised concerns about the anti-inflammatory effects of melatonin, specifically those comprising the reduction of the pathological changes in the tissues, attenuation of the development of O2-induced hyperalgesia and blockage of cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) induction (14). Additionally, melatonin provides protective effects through the autophagy pathway in the Senescence Accelerated Mouse-Prone 8 (SAMP8) mice (15). It seems that melatonin plays an effective neuroprotective role in SAH management (16, 17). However, this argument is inconsistent (18). The current study aims to evaluate and validate the efficacy of melatonin administration on experimental SAH animals. The related factors of research design that could shape the results will also be analyzed. Further, this preclinical study may offer support for the future clinical trial design of the melatonin treatment following SAH.
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