Department of Pharmacy, “G. d’Annunzio” University, via dei Vestini 31, 66013 Chieti, Italy.
Curr Med Chem. 2013 Feb 1;20(6):735-50.
Ischemic insults and neurodegenerative diseases are by far the leading cause of mortality and disability. Whole-body hypoperfusion, as it occurs in polytraumatic and hemorrhagic shock, is alike an increasingly frequent condition, especially due to traffic accidents, wars and acts of terrorism. It is now clearly established that inflammatory processes play a fundamental role in the pathophysiology of both hypoperfusion/ischemia damage (be it generalized to the whole body, as in the case of shock, or limited to individual organs) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis). On the other hand, concurrent animal and human data show that melanocortin peptides with agonist activity at melanocortin MC3/MC4 receptors are highly effective in different shock conditions as well as in conditions of ischemia/ischemia-reperfusion of individual organs (heart, brain, intestine, kidney, etc.), and accumulating evidence indicates that such effects of melanocortins are mostly due to quite peculiar antiinflammatory mechanisms. Melanocortins have also long been known (i) to exert important neurotrophic effects, not only during fetal development but also in adulthood, in different animal models of brain lesions; (ii) to reduce the morphological correlates of brain aging; (iii) to retard the behavioral deficits that develop during the aging process. Moreover, recent data from different laboratories show that after brain ischemic episodes melanocortins activate the transcription of neurotrophins and their receptors in the cerebral cortex and in the hippocampus, and increase the proliferation of progenitor neuron cells. The above arguments support the view that pharmacokinetically suitable agonists at MC3/MC4 melanocortin receptors may represent a completely innovative class of drugs for an effective treatment of both ischemic and neurodegenerative diseases.
缺血性损伤和神经退行性疾病是目前导致死亡和残疾的主要原因。全身性低灌注，如多发创伤和失血性休克中发生的情况，同样是一种越来越常见的情况，尤其是由于交通事故、战争和恐怖主义行为。现在已经明确的是，炎症过程在低灌注/缺血性损伤的病理生理学中起着基本作用（无论是全身性的，如休克情况下，还是局限于单个器官），以及神经退行性疾病（阿尔茨海默病、帕金森病、多发性硬化症、肌萎缩侧索硬化症）。另一方面，同时进行的动物和人体数据表明，具有黑色素皮质素 MC3/MC4 受体激动活性的黑色素皮质素肽在不同的休克状态以及单个器官（心脏、大脑、肠道、肾脏等）的缺血/再灌注状态下非常有效，并且越来越多的证据表明，黑色素皮质素的这种作用主要是由于其独特的抗炎机制。黑色素皮质素一直以来都被认为（i）在不同的脑损伤动物模型中，不仅在胎儿发育过程中，而且在成年期也具有重要的神经营养作用；（ii）减少脑老化的形态学相关性；（iii）延缓衰老过程中出现的行为缺陷。此外，来自不同实验室的最新数据表明，在脑缺血发作后，黑色素皮质素会激活大脑皮层和海马体中的神经营养因子及其受体的转录，并增加祖细胞神经元的增殖。上述观点支持这样一种观点，即具有合适药代动力学的 MC3/MC4 黑色素皮质素受体激动剂可能代表一类全新的药物，可有效治疗缺血性和神经退行性疾病。
