benzofurans and Encephalitis

Neuroinflammation is often associated with astrocyte and microglial activations particularly in Parkinson's disease (PD) and other brain damage such as Alzheimer's disease. Therefore, the modulation of glial activation offers a possible target for treating PD-associated pathologies. Here, we evaluated the neuroprotective effects of usnic acid, a naturally occurring dibenzofuran derivative found in several lichen species in an acute mouse model of PD. Male mice were administered with vehicle or usnic acid (5 or 25 mg/kg) for 10 consecutive days, and then on day 11, MPTP (20 mg/kg, i.p.) was administered four times (with 2hrs intervals between injections) to induce PD pathologies. It was found that MPTP-induced motor dysfunction and neuronal loss were ameliorated in the usnic acid-treated mice versus vehicle-treated controls. Further study revealed that usnic acid effectively inhibited MPP

Topics: Animals; Anti-Inflammatory Agents; Benzofurans; Brain; Disease Models, Animal; Dopaminergic Neurons; Encephalitis; Male; Mice, Inbred C57BL; Neuroglia; Neuroprotective Agents; Nitric Oxide Synthase Type II; Parkinsonian Disorders; Rotarod Performance Test

Microglia can be activated to become the classic phenotype (M1) or alternative phenotype (M2), which play an important role in regulating neuroinflammatory response and tissue repair after ischemic stroke. CD21, a novel phthalide derivative, is a potential neuroprotectant against ischemic brain injury. The present study further investigated the effects of CD21 on post-ischemic microglial polarization and the underlying mechanisms. Transient middle cerebral artery occlusion (tMCAO) was used as a mouse model of ischemic stroke, while BV2 cells stimulated with conditioned medium collected from oxygen-glucose deprivation-treated HT22 cells were used in in vitro ischemic studies. The current results showed that CD21 dose-dependently and significantly improved neurological outcomes in tMCAO mice. Biochemical analyses revealed that CD21 decreased the expression of M1 phenotype markers (CD86, interleukin-1β and inducible nitric oxide synthase) and increased the expression of M2 phenotype markers (CD206, interleukin-10 and YM1/2) in both ischemic brain tissues and BV2 cells. Meanwhile, CD21 decreased the production of proinflammatory cytokines (interleukin-1β, interleukin-6 and tumor necrosis factor-α), promoted the release of the antiinflammatory cytokine (interleukin-10), and enhanced the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) in ischemic brain tissue and BV2 cells. Furthermore, the AMPK inhibitor (compound C) reversed these effects of CD21 in BV2 cells. These findings indicate that CD21 alleviates post-ischemic neuroinflammation through induction of microglial M2 polarization that is at least in part medicated by AMPK activation, suggesting that CD21 may be a promising candidate for protecting against ischemic brain injury.

Topics: 4-Butyrolactone; AMP-Activated Protein Kinases; Animals; Behavior, Animal; Benzofurans; Brain Ischemia; Cell Line; Cell Polarity; Cytokines; Dose-Response Relationship, Drug; Encephalitis; Enzyme Activation; Infarction, Middle Cerebral Artery; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroprotective Agents; Phenotype; Psychomotor Performance

Complex regional pain syndrome type 1 (CRPS-I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post-ischemia pain (CPIP) as a model of CRPS-I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS-I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS-I in the setting of ischemia and reperfusion injury.

Topics: Animals; Benzofurans; CX3C Chemokine Receptor 1; Disease Models, Animal; Encephalitis; Epidermis; Hyperalgesia; Ischemia; Male; Microglia; Pain; Piperidines; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Receptors, Chemokine; Reflex Sympathetic Dystrophy; Spinal Cord Dorsal Horn