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Histaminergic system in brain disorders: lessons from the translational approach and future perspectives

Melatonin as nephroprotective adjunct in clinical studies The safety and efficacy of melatonin have been extensively investigated in several clinical trials that documented its potential therapeutic usefulness in variety of disease conditions.137 There has been a major drive in patent applications claiming the therapeutic exploitation of melatonin and its analogues with pre-dominant focus on cancer, neurological, immunological and metabolic diseases.138 Interestingly, the proven therapeutic potential of melatonin or its use as a therapeutic adjunct resulted into the successful development of its hybrid ligands such as with tacrine in Alzheimer's.139 There are some clinical interventions that highlight the relationship between nocturnal secretion of melatonin and renal physiology and suggest the role of melatonin to reduce the renal blood flow and urine concentration of sodium, potassium, urate and chloride ions.140,141 These temporal changes in renal function may suggest the role of melatonin to influence the development of renal colic.142 Moreover, the allelic variation of Melatonin receptor 1A (MTNR1A) gene is also associated with pre-disposition to calcium nephrolithiasis.143 Interestingly, the development or severity of chronic kidney disease (CKD) accompany significant impairments in endogenous melatonin secretions that may warrant its exogenous administration.144 Recently, the effect of exogenous melatonin supplementation has been assessed for its therapeutic benefits in CKD associated risk factors and sleep disorders.145,146 Melatonin co-administration has been found to enhance the survival rate and efficacy of IL-2 immunotherapy by attenuating the immunosuppressive effect of opioids without compromising its analgesic effect in palliative care of metastatic renal cancer patients.147 Pre-treatment of melatonin has also been found to ameliorate the iron and erythropoietin-induced oxidative stress in anemic patients with end-stage renal failure.148 A double-blind placebo controlled clinical trial has revealed that concomitant administration of melatonin and zinc acetate ameliorate the poorly controlled microalbuminuria induced renal failure in type 2 diabetes mellitus patients treated with biguanides.149 Moreover, there is an ongoing randomized, double-blind, placebo controlled clinical trial to address the nephroprotective potential of melatonin in polymixin B induced nephrotoxicity.150 Despite the impressive pre-clinical data, there are still limited clinical interventions that address the putative role of melatonin in amelioration of drug-induced nephrotoxicity