Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia

Abstract

We have previously shown that melatonin reduces infarct volumes and enhances neurobehavioral and electrophysiological recoveries following transient middle cerebral artery (MCA) occlusion in rats. In the study, we examined whether melatonin would display neuroprotection against neuronal, axonal and oligodendrocyte pathology after 24 hr of reperfusion following 1 hr of MCA occlusion in mice. Melatonin (5 mg/kg) or vehicle was given intraperitoneally at the commencement of reperfusion. Neurological deficits were assessed 24 hr after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein and microtubule-associated protein tau-1 immunohistochemistry to identify postischemic disrupted axonal flow and oligodendrocyte pathology, respectively. Oxidative damage was assessed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE) immunohistochemistry. Relative to controls, melatonin-treated animals not only had a significantly reduced volume of gray matter infarction by 42% (P<0.001), but also exhibited a decreased score of axonal damage by 42% (P<0.001) and a reduction in the volume of oligodendrocyte pathology by 58% (P<0.005). Melatonin-treated animals also had significantly reduced immunopositive reactions for 8-OHdG and 4-HNE by 53% (P<0.001) and 49% (P<0.001), respectively. In addition, melatonin improved sensory and motor neurobehavioral outcomes by 47 and 30%, respectively (P<0.01). Thus, delayed (1 hr) treatment with melatonin reduced both gray and white matter damage and improved neurobehavioral outcomes following transient focal cerebral ischemia in mice. The finding of reduced oxidative damage observed with melatonin suggests that its major mechanisms of action are mediated through its antioxidant and radical scavenging activity.

A Review of Melatonin, Its Receptors and Drugs

“…Neurological disorders which have been reported to be improved by administration of melatonin are as follows: Parkinsonism [10], Alzheimer's disease [11], brain edema and traumatic brain injury [12], alcoholism [13], depression [14], cerebral ischemia [15], hyperhomocysteinuria [16], glioma [17] and phenylketonuria [18]. Alzheimer's disease is an age-related progressive neurodegenerative disorder, characterized with loss of cognitive functions, dementia and other neurobiological findings [2,19].…”

Delayed Treatment with Carboxy-PTIO Permits a 4-h Therapeutic Window of Opportunity and Prevents Against Ischemia-Induced Energy Depletion Following Permanent Focal Cerebral Ischemia in Mice

“…Focal cerebral ischemia was employed by intra-arterial suture occlusion of the proximal right middle cerebral artery (MCA) [7,[16][17][18][19][20][21]. Briefly, the bifurcation of the right common carotid artery was exposed under an operative microscope.…”

Differential effects of early postinjury treatment with neuroprotective drugs in a mouse model using diffuse reflectance spectroscopy

“…A possible reason for this discrepancy with the present study could be the difference in dose and timing of melatonin administration, injury model, and measurement setup. Nonetheless, other studies also showed reduced brain edema 82,83 and its effectiveness in diverse models of experimental traumatic central nervous system. 74,84,85 3.5 Experiment #5: Minocycline Test…”