jwh-133 and Intracranial-Hemorrhages

Microglia play dual roles after germinal matrix hemorrhage, and the neurotrophic phenotype maybe neuroprotective. However, the phenotype transformation and the way by which neuron-microglia dialogue remain unclear. We raise the hypothesis that a cannabinoid receptor2 agonist (JWH133) accelerates the CX3CR1

Topics: Animals; Animals, Newborn; Brain Injuries; Brain-Derived Neurotrophic Factor; Camphanes; Cannabinoids; CX3C Chemokine Receptor 1; Disease Models, Animal; Female; In Vitro Techniques; Intracranial Hemorrhages; Male; Microglia; Nerve Tissue Proteins; Pregnancy; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Chemokine; RNA, Small Interfering; Up-Regulation

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

Germinal matrix hemorrhage (GMH) is one of the most common and devastating cerebrovascular events that affect premature infants, resulting in a significant socioeconomic burden. However, GMH has been largely unpreventable, and clinical treatments are mostly inadequate. In the present study, we tested the hypothesis that JWH133, a selective CB2 receptor agonist, could attenuate brain injury and neurological deficits in a clostridial collagenase VII induced GMH model in seven-day-old (P7) S-D rat pups. Up to 1h post-injury, the administration of JWH133 (1mg/kg, intraperitoneal injection) significantly attenuated brain edema at 24h post-GMH, which was reversed by a selective CB2R antagonist, SR144528 (3mg/kg, intraperitoneal injection). Long-term brain morphology and neurofunctional outcomes were also improved. In contrast, JWH133 did not have a noticeable effect on the hematoma volume during the acute phase. These data also showed that microglia activation and inflammatory cytokine (TNF-α) release were significantly inhibited by JWH133 after GMH. This current study suggests a potential clinical utility for CB2R agonists as a potential therapy to reduce neurological injury and improve patient outcomes after GMH.

Topics: Acute Disease; Animals; Brain; Brain Edema; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Chronic Disease; Disease Models, Animal; Female; Intracranial Hemorrhages; Male; Microglia; Movement; Neuroprotective Agents; Pyrazoles; Random Allocation; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Tumor Necrosis Factor-alpha

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