Melatonin combined with exercise cannot alleviate cerebral injury in a rat model of focal cerebral ischemia/reperfusion injury

Previous studies have demonstrated that melatonin combined with exercise can alleviate secondary damage after spinal cord injury in rats. Therefore, it is hypothesized that melatonin combined with exercise can also alleviate ischemic brain damage. In this study, adult rats were subjected to right middle cerebral artery occlusion after receiving 10 mg/kg melatonin or vehicle subcutaneously twice daily for 14 days. Forced exercise using an animal treadmill was performed at 20 m/min for 30 minutes per day for 6 days prior to middle cerebral artery occlusion. After middle cerebral artery occlusion, each rat received melatonin combined with exercise, melatonin or exercise alone equally for 7 days until sacrifice. Interestingly, rats receiving melatonin combined with exercise exhibited more severe neurological deficits than those receiving melatonin or exercise alone. Hypoxia-inducible factor la mRNA in the brain tissue was upregulated in rats receiving melatonin combined with exercise. Similarly, microtubule associated protein-2 mRNA expression was significantly upregulated in rats receiving melatonin alone. Chondroitin sulfate proteoglycan 4 （NG2） mRNA expression was significantly decreased in rats receiving melatonin combined with exercise as well as in rats receiving exercise alone. Furthermore, neural cell loss in the primary motor cortex was significantly reduced in rats receiving melatonin or exercise alone, but the change was not observed in rats receiving melatonin combined with exercise. These findings suggest that excessive intervention with melatonin, exercise or their combination may lead to negative effects on ischemia/reperfusion-induced brain damage.

Dissecting the multifactorial nature of demyelinating disease

Chondroitin sulfate proteoglycan-4（CSPG4） is a surface component of two key cell types（oligodendrocyte progenitor cells（OPCs） and myeloid cells） present in lysolecithin-induced lesions in mouse spinal cord.Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair：（1） OPC and myeloid-specific ablation of CSPG4,and（2） transplantation of enhanced green fluorescent protein（EGFP）-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia.Ablation of CSPG4 in OPCs does not affect myelin damage,but decreases myelin repair,due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination.Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions,resulting in smaller initial lesions,but also in significantly diminished myelin repair.In the absence of macrophage recruitment,OPC proliferation is greatly impaired,again leading to decreased generation of myelinating oligodendrocytes.Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis.Microglia are not able to substitute for macrophages in promoting OPC proliferation.An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor α（PDGFRα） ＋ macrophages that may prolong damage.