am-630 and Brain-Edema

Germinal matrix hemorrhage (GMH) is the most common neurological disease of premature newborns leading to detrimental neurological sequelae. Minocycline has been reported to play a key role in neurological inflammatory diseases by controlling some mechanisms that involve cannabinoid receptor 2 (CB2R). The current study investigated whether minocycline reduces neuroinflammation and protects the brain from injury in a rat model of collagenase-induced GMH by regulating CB2R activity. To test this hypothesis, the effects of minocycline and a CB2R antagonist (AM630) were evaluated in male rat pups that were post-natal day 7 (P7) after GMH. We found that minocycline can lead to increased CB2R mRNA expression and protein expression in microglia. Minocycline significantly reduced GMH-induced brain edema, microglial activation, and lateral ventricular volume. Additionally, minocycline enhanced cortical thickness after injury. All of these neuroprotective effects of minocycline were prevented by AM630. A cannabinoid CB2 agonist (JWH133) was used to strengthen the hypothesis, which showed the identical neuroprotective effects of minocycline. Our study demonstrates, for the first time, that minocycline attenuates neuroinflammation and brain injury in a rat model of GMH, and activation of CBR2 was partially involved in these processes.

Topics: Animals; Animals, Newborn; Brain Edema; Calcium-Binding Proteins; Cannabinoids; Cerebral Ventricles; Cytokines; Enzyme-Linked Immunosorbent Assay; Indoles; Inflammation; Intracranial Hemorrhages; Magnetic Resonance Imaging; Male; Microfilament Proteins; Microglia; Minocycline; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

Traumatic brain injury (TBI) and its consequences represent one of the leading causes of death in young adults. This lesion mediates glial activation and the release of harmful molecules and causes brain edema, axonal injury, and functional impairment. Since glial activation plays a key role in the development of this damage, it seems that controlling it could be beneficial and could lead to neuroprotective effects. Recent studies show that minocycline suppresses microglial activation, reduces the lesion volume, and decreases TBI-induced locomotor hyperactivity up to 3 months. The endocannabinoid system (ECS) plays an important role in reparative mechanisms and inflammation under pathological situations by controlling some mechanisms that are shared with minocycline pathways. We hypothesized that the ECS could be involved in the neuroprotective effects of minocycline. To address this hypothesis, we used a murine TBI model in combination with selective CB1 and CB2 receptor antagonists (AM251 and AM630, respectively). The results provided the first evidence for the involvement of ECS in the neuroprotective action of minocycline on brain edema, neurological impairment, diffuse axonal injury, and microglial activation, since all these effects were prevented by the CB1 and CB2 receptor antagonists.

Topics: Animals; Axons; Brain; Brain Edema; Brain Injuries; Cannabinoid Receptor Antagonists; Indoles; Male; Mice; Microglia; Minocycline; Motor Activity; Neuroprotective Agents; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

Microglia accumulation plays detrimental roles in the pathology of germinal matrix hemorrhage (GMH) in the immature preterm brain. However, the underlying mechanisms remain poorly defined. Here, we investigated the effects of a cannabinoid receptor 2 (CB2R) agonist on microglia proliferation and the possible involvement of the mitogen-activated protein kinase (MAPK) family pathway in a collagenase-induced GMH rat model and in thrombin-induced rat microglia cells. We demonstrated that activation of CB2R played a key role in attenuating brain edema, neuronal degeneration, microglial accumulation and the phosphorylated extracellular signal-regulated kinase (p-ERK) protein level 24 h following GMH. In vitro, Western blot analysis and immunostaining indicated that ERK and P38 phosphorylation levels in microglia stimulated by thrombin were decreased after JWH-133 (CB2R selective agonist) treatment in a concentration-dependent manner. Microglia proliferation (EDU + microglia) and inflammatory and oxidative stress responses were attenuated by UO126 (ERK pathway inhibitor) 24 h after thrombin stimulation, an activity that was prevented by AM630 (CB2R selective antagonist). Overall, these findings suggest that activation of the endocannabinoid system might attenuate inflammation-induced secondary brain injury after GMH in rats by reducing microglia accumulation through a mechanism involving ERK dephosphorylation. Enhancing CB2R activation is a potential treatment to slow down the course of GMH in preterm newborns.

Topics: Animals; Brain; Brain Edema; Butadienes; Cannabinoids; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Indoles; Intracranial Hemorrhages; Male; Microglia; Nerve Degeneration; Neuroimmunomodulation; Nitriles; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Random Allocation; Receptor, Cannabinoid, CB2; Thrombin