Evidence that membrane‐bound G protein‐coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral ischemia

Abstract

Melatonin is synthesized and released by the pineal gland in a circadian rhythm, and many of its peripheral actions are mediated via membrane MT1 and MT2 receptors. Apart from its metabolic functions, melatonin is a potent neuroprotective molecule owing to its antioxidative actions. The roles of MT1 and MT2 in the neuroprotective effects of melatonin and cell signaling after cerebral ischemia remain unknown. With the use of MT1 and MT2 knockout (mt1/2(-/-) ) mice treated with melatonin, we evaluated brain injury, edema formation, inducible nitric oxide synthase (iNOS) activity, and signaling pathways, including CREB, ATF-1, p21, Jun kinase (JNK)1/2, p38 phosphorylation, resulting from ischemia/reperfusion injury. We show that the infarct volume and brain edema do not differ between mt1/2(-/-) and wild-type (WT) animals, but melatonin treatment decreases infarct volume in both groups and brain edema in WT animals after middle cerebral artery occlusion. Notably, melatonin's neuroprotective effect was even more pronounced in mt1/2(-/-) animals compared to that in WT animals. We also demonstrate that melatonin treatment decreased CREB, ATF-1, and p38 phosphorylation in both mt1/2(-/-) and WT mice, while p21 and JNK1/2 were reduced only in melatonin-treated WT animals in the ischemic hemisphere. Furthermore, melatonin treatment lowered iNOS activity only in WT animals. We provide evidence that the absence of MT1 and MT2 has no unfavorable effect on ischemic brain injury. In addition, the neuroprotective effects of melatonin appear to be mediated through a mechanism independent of its membrane receptors. The underlying mechanism(s) should be further studied using selective melatonin receptor agonists and antagonists.

Caffeine increases mitochondrial function and blocks melatonin signaling to mitochondria in Alzheimer's mice and cells

“…But melatonin did not block activation of CREB in neurons of the suprachiasmatic nucleus stimulated by glutamate or in astrocytes. Melatonin treatment decreased activated CREB levels independently of melatonin receptors in a murine model of focal cerebral ischemia (Kilic et al, 2012). Melatonin signaling has been shown to stimulate CREB activity in astrocytes (Kong et al, 2008) and in cells from the dentate gyrus (Yoo et al, 2012).…”

A review of melatonin as a suitable antioxidant against myocardial ischemia–reperfusion injury and clinical heart diseases

“…In mammals, some of melatonin's actions involve two high-affinity G protein-coupled receptors, MT1 and MT2, which are widely expressed in multiple tissues and organs, including the retina [60], brain [19], and cardiovascular system [61,62]. The link between the melatonin receptor and JAK/STAT pathway has been proven in a few studies.…”

“…Melatonin, a circadian hormone with marked antioxidant properties [4][5][6][7][8], has been shown to protect against ischemia-reperfusion (IR) injury in various organs including heart [9][10][11][12], liver [13][14][15][16], brain [17][18][19], kidney [20], intestine [21], lung [22], and testis [23]. Moreover, numerous studies suggest that melatonin plays a significant role in hypertension [24,25], heart failure [12,26], drug-induced myocardial injury [27,28], and atherosclerosis [29,30].…”

Is Melatonin Protective in Contrast Material Related Renal Failure?

“…In the absence of tubular dysfunction, its serum level reflects glomerular filtration and can be used as a functional marker for acute and chronic changes in GFR (12,13) Melatonin and its metabolites force the antioxidant system to work through free radicals. An antioxidant enhances the synthesis of enzymes and increases the efficiency of other antioxidants (14). Wang et al showed that protection against cardiopulmonary bypass-induced renal injury could be ensured under the antioxidant effect of melatonin (15,17).…”