piperidines and Encephalitis

To treat intractable cases of autoimmune encephalitis, the need for novel immunotherapy that penetrates the blood-brain barrier (BBB) is increasing. Tofacitinib is a Janus kinase (JAK) inhibitor used to treat refractory immune-mediated diseases that effectively penetrates the BBB. Accordingly, tofacitinib could be a new option for patients with refractory autoimmune encephalitis. Patients treated with tofacitinib were selected from Seoul National University Hospital cohort for autoimmune encephalitis from April 2019 until July 2020. We retrospectively analyzed the efficacy of tofacitinib in patients with autoimmune encephalitis who showed insufficient responses to multimodal conventional immunotherapies. Tofacitinib was administered orally at a dose of 5 mg twice daily. A total of eight patients were treated with tofacitinib; two had good responses (clinical global impression-improvement score [CGI-I] = 1 or 2), three had partial responses (CGI-I = 3), and three showed no significant improvements (CGI-I = 4) in response to tofacitinib. The two good responders showed the improvement of chronic autoimmune meningoencephalitis and the cessation of the new-onset refractory status epilepticus in anti-myelin oligodendrocyte glycoprotein (MOG)-associated disorder, which was previously intractable to anesthetics and the other immunotherapies. No patients had serious side effects. Our findings suggest the potential of tofacitinib as a therapeutic option for central nervous system autoimmune diseases.

Topics: Adult; Aged; Autoantibodies; Encephalitis; Female; Hashimoto Disease; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Treatment Outcome; Young Adult

Neuroinflammation is considered to be a critical component in the pathological process after intracerebral hemorrhage (ICH). Microglia are the foremost and earliest inflammatory cells participating in the pathological process of ICH. AdipoRon is the agonist of AdipoR1 (Adiponectin receptor 1), which enhances P-AMPK (phosphorylated AMP-activated protein kinase) activation. The activated AMPK facilitates microglia/macrophage polarization by driving the cell state from pro-inflammatory M1 state to anti-inflammatory M2 state. The study aims to investigate the role of AdipoRon in microglial polarization and neuroprotection after ICH. The experimental ICH model was established by autologous blood injection, and the treated group was done additionally by intraperitoneal injection of drugs. Flow cytometry analysis and immunofluorescence staining were performed to quantify the ratio of M1 to M2 phenotype microglia in mice. The present study indicated that AdipoRon could ameliorate neurological deficits in mice after ICH. Flow cytometric analysis demonstrated that the proportion of CD206

Topics: Adenylate Kinase; Animals; Anti-Inflammatory Agents; Cerebral Hemorrhage; Disease Models, Animal; Encephalitis; Male; Mice; Neurons; Phosphorylation; Piperidines; Receptors, Adiponectin; Signal Transduction

Alzheimer's disease (AD) is the main cause of dementia and a major health issue worldwide. The complexity of the pathology continues to challenge its comprehension and the implementation of effective treatments. In the last decade, a number of possible targets of intervention have been pointed out, among which the stimulation of 5-HT

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Aniline Compounds; Animals; Behavior, Animal; Disease Models, Animal; Encephalitis; Entorhinal Cortex; Learning; Male; Memory; Mice, Transgenic; Neuroglia; Piperidines; Plaque, Amyloid; Serotonin 5-HT4 Receptor Agonists

Aberrant activation of toll-like receptors (TLRs), key components of the innate immune system, has been proposed to underlie and exacerbate a range of central nervous system disorders. Increasing evidence supports a role for the endocannabinoid system in modulating inflammatory responses including those mediated by TLRs, and thus this system may provide an important treatment target for neuroinflammatory disorders. However, the effect of modulating endocannabinoid tone on TLR-induced neuroinflammation in vivo and associated behavioural changes is largely unknown. The present study examined the effect of inhibiting fatty acid amide hydrolyase (FAAH), the primary enzyme responsible for the metabolism of anandamide (AEA), in vivo on TLR4-induced neuroimmune and behavioural responses, and evaluated sites and mechanisms of action. Systemic administration of the FAAH inhibitor PF3845 increased levels of AEA, and related FAAH substrates N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA), in the frontal cortex and hippocampus of rats, an effect associated with an attenuation in the expression of pro- and anti-inflammatory cytokines and mediators measured 2hrs following systemic administration of the TLR4 agonist, lipopolysaccharide (LPS). These effects were mimicked by central i.c.v. administration of PF3845, but not systemic administration of the peripherally-restricted FAAH inhibitor URB937. Central antagonism of TRPV1 significantly attenuated the PF3845-induced decrease in IL-6 expression, effects not observed following antagonism of CB

Topics: Amidohydrolases; Animals; Encephalitis; Illness Behavior; Lipopolysaccharides; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Toll-Like Receptor 4; TRPV Cation Channels

In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.. The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.. We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.. These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.

Topics: Amyotrophic Lateral Sclerosis; Animals; Benzamides; Cell Death; Disease Models, Animal; Disease Progression; Encephalitis; Humans; Male; Motor Neurons; Mutation; Neuroglia; Paralysis; Piperidines; Protein Kinase Inhibitors; Pyridines; Rats; Rats, Transgenic; Spinal Cord; Superoxide Dismutase; Thiazoles

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

Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: Spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer's disease-like toxicity in the rodent brain.

Topics: Adenine; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents, Non-Steroidal; Butyrates; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Encephalitis; Enzyme Inhibitors; Hippocampus; Hydrocarbons, Halogenated; Ibuprofen; Indans; Learning Disabilities; Male; Memory Disorders; Mice; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Piperidines

Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Benzodioxoles; Brain; Calcium-Binding Proteins; Disease Models, Animal; Encephalitis; Enzyme Inhibitors; Interferon-gamma; Mice; Mice, Transgenic; Microfilament Proteins; Monoacylglycerol Lipases; Neuroglia; Nitrites; Piperidines

Tetramethylenedisulfotetramine (TETS) is a potent convulsant poison for which there is currently no approved antidote. The convulsant action of TETS is thought to be mediated by inhibition of type A gamma-aminobutyric acid receptor (GABAAR) function. We, therefore, investigated the effects of post-exposure administration of diazepam, a GABAAR positive allosteric modulator, on seizure activity, death and neuroinflammation in adult male Swiss mice injected with a lethal dose of TETS (0.15mg/kg, ip). Administration of a high dose of diazepam (5mg/kg, ip) immediately following the second clonic seizure (approximately 20min post-TETS injection) effectively prevented progression to tonic seizures and death. However, this treatment did not prevent persistent reactive astrogliosis and microglial activation, as determined by GFAP and Iba-1 immunoreactivity and microglial cell morphology. Inhibition of soluble epoxide hydrolase (sEH) has been shown to exert potent anti-inflammatory effects and to increase survival in mice intoxicated with other GABAAR antagonists. The sEH inhibitor TUPS (1mg/kg, ip) administered immediately after the second clonic seizure did not protect TETS-intoxicated animals from tonic seizures or death. Combined administration of diazepam (5mg/kg, ip) and TUPS (1mg/kg, ip, starting 1h after diazepam and repeated every 24h) prevented TETS-induced lethality and influenced signs of neuroinflammation in some brain regions. Significantly decreased microglial activation and enhanced reactive astrogliosis were observed in the hippocampus, with no changes in the cortex. Combining an agent that targets specific anti-inflammatory mechanisms with a traditional antiseizure drug may enhance treatment outcome in TETS intoxication.

Topics: Animals; Anti-Inflammatory Agents; Anticonvulsants; Brain; Brain Waves; Bridged-Ring Compounds; Diazepam; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Electroencephalography; Encephalitis; Enzyme Inhibitors; Epoxide Hydrolases; GABA Modulators; Male; Mice; Phenylurea Compounds; Piperidines; Seizures; Time Factors

JZL184 is a selective inhibitor of monoacylglycerol lipase (MAGL), the enzyme that preferentially catabolizes the endocannabinoid 2-arachidonoyl glycerol (2-AG). Here, we have studied the effects of JZL184 on inflammatory cytokines in the brain and plasma following an acute immune challenge and the underlying receptor and molecular mechanisms involved.. JZL184 and/or the CB₁ receptor antagonist, AM251 or the CB₂ receptor antagonist, AM630 were administered to rats 30 min before lipopolysaccharide (LPS). 2 h later cytokine expression and levels, MAGL activity, 2-AG, arachidonic acid and prostaglandin levels were measured in the frontal cortex, plasma and spleen.. JZL184 attenuated LPS-induced increases in IL-1β, IL-6, TNF-α and IL-10 but not the expression of the inhibitor of NFkB (IκBα) in rat frontal cortex. AM251 attenuated JZL184-induced decreases in frontal cortical IL-1β expression. Although arachidonic acid levels in the frontal cortex were reduced in JZL184-treated rats, MAGL activity, 2-AG, PGE₂ and PGD₂ were unchanged. In comparison, MAGL activity was inhibited and 2-AG levels enhanced in the spleen following JZL184. In plasma, LPS-induced increases in TNF-α and IL-10 levels were attenuated by JZL184, an effect partially blocked by AM251. In addition, AM630 blocked LPS-induced increases in plasma IL-1β in the presence, but not absence, of JZL184.. Inhibition of peripheral MAGL in rats by JZL184 suppressed LPS-induced circulating cytokines that in turn may modulate central cytokine expression. The data provide further evidence for the endocannabinoid system as a therapeutic target in treatment of central and peripheral inflammatory disorders.

Topics: Animals; Anti-Anxiety Agents; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Benzodioxoles; Cannabinoid Receptor Antagonists; Cytokines; Encephalitis; Endocannabinoids; Enzyme Inhibitors; Frontal Lobe; Glycerides; Lipopolysaccharides; Male; Monoacylglycerol Lipases; Nerve Tissue Proteins; Peritonitis; Piperidines; Prostaglandins; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Spleen

The present study was planned to investigate the effect of anti-cholinesterase drugs donepezil and neostigmine on neuroinflammation induced by intracerebroventricular administration of lipopolysaccharide (LPS, 50 microg) in rat. Proinflammatory cytokines (TNF-alpha and IL-1beta), expressions of iNOS and COX-2, acetylcholinesterase activity, malondialdehyde and reduced glutathione were studied in different brain regions at 24h of LPS injection. Donepezil was found to decrease the LPS-induced AChE activity and oxidative stress in all the brain regions. It also inhibited the LPS-induced proinflammatory cytokines and iNOS expression but did not affect the increased COX-2 expression whereas neostigmine treatment had no effect on LPS-induced proinflammatory cytokines. Methyllycaconitine (MLA), a alpha7 nicotinic acetylcholine receptor antagonist, significantly antagonized the donepezil mediated inhibition of LPS-induced proinflammatory cytokines, indicating that alpha7 nicotinic acetylcholine receptor subunit was playing a role in regulation of neuroinflammation. The phosphorylation of Akt, an effector of PI3K, increased with donepezil treatment. These results suggest that increased cholinergic activity in brain by donepezil prevents LPS-induced neuroinflammation via alpha7-nAChRs, followed by the PI3K-Akt pathway and this system may form the basis for the development of novel agents for reversing neuroinflammation or provide new indications for existing drugs.

Topics: Acetylcholinesterase; alpha7 Nicotinic Acetylcholine Receptor; Animals; Anti-Inflammatory Agents; Brain; Cholinesterase Inhibitors; Cyclooxygenase 2; Donepezil; Encephalitis; Glutathione; Indans; Inflammation Mediators; Interleukin-1beta; Lipopolysaccharides; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Tumor Necrosis Factor-alpha

Donepezil is a reversible and noncompetitive cholinesterase inhibitor. The drug is considered as a first-line treatment in patients with mild to moderate Alzheimer's disease. Recently, anti-inflammatory and neuroprotective effects of the drug have been reported. "Cholinergic anti-inflammation pathway" has major implications in these effects. Here, we present evidence that donepezil at 5-20 microM directly acts on microglial cells to inhibit their inflammatory activation. Our conclusion is based on the measurement of nitric oxide and proinflammatory mediators using purified microglia cultures and microglia cell lines: donepezil attenuated microglial production of nitric oxide and tumor necrosis factor (TNF)-alpha, and suppressed the gene expression of inducible nitric oxide synthase, interleukin-1 beta, and TNF-alpha. Subsequent studies showed that donepezil inhibited a canonical inflammatory NF-kappaB signaling. Microglia/neuroblastoma coculture and animal experiments supported the anti-inflammatory effects of donepezil. Based on the studies using nicotinic acetylcholine receptor antagonists, the donepezil inhibition of microglial activation was independent of acetylcholine and its receptor. Thus, inflammatory activation signaling of microglia may be one of the direct targets of donepezil in the central nervous system. It should be noted, however, that there is a large gap between the therapeutic dose of the drug used clinically and the concentration of the drug that exerts the direct action on microglial cells.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Cell Line, Tumor; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Donepezil; Encephalitis; Gene Expression; Indans; Interleukin-1beta; Mice; Microglia; Neuroimmunomodulation; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Piperidines; Rats; Signal Transduction; Tumor Necrosis Factor-alpha

Cerebral ischemia/reperfusion injury is characterized by the development of inflammatory response, in which vascular macrophages and endogenous microglia are involved. Recent studies showed marked induction of hematopoietic prostaglandin D synthase (HPGDS) after ischemic/reperfusion injury and its localization in microglia, but the molecular mechanism(s) of HPGDS actions in cerebral ischemia is not clear. To clarify the role of HPGDS in cerebral ischemia, C57BL/6 mice and bone marrow chimera mice with cerebral ischemia/reperfusion injury were treated with (4-benzhydryloxy-(1) {3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a specific inhibitor of HPGDS. The bone marrow chimera mice exhibit expression of enhanced green fluorescent protein (EGFP) in bone marrow/blood-derived monocytes/macrophages. Mice were subjected to ischemia/reperfusion and either treated with HQL-79 (n=44) or vehicle (n=44). Brain sections prepared at 72 h and 7 days after reperfusion were analyzed for neuronal nuclei (NeuN), HPGDS, ionized calcium-binding adapter molecule 1 (Iba1), inducible NO synthase (iNOS), nitrotyrosine, nuclear factor kappa B (NF-kB) and cyclooxygenase-2 (COX-2). The mortality rate (80%) and infarct size were larger in HQL-79- than vehicle-treated mice (58.7+/-8.5 versus 45.2+/-4.9 mm(3); mean+/-SEM, P<0.0001) at 7 days after reperfusion. HQL-79 reduced NeuN expression in the transition area and Iba1 expression (P<0.0001) in the ischemic peri- and penumbra area, but increased COX-2 (P<0.05) and NF-kB expression (P<0.05) in ischemic penumbra and increased formation of nitrotyrosine (P<0.0001) and iNOS (P<0.0001) in the ischemic core area at 72 h and 7 days after reperfusion. In EGFP chimera mice, HQL-79 increased the migration of Iba1/EGFP-positive bone marrow-derived monocytes/macrophages, and simultaneously upregulated iNOS expression in the ischemic core area (P<0.0001), but increased intrinsic microglia/macrophages in ischemic peri-area and penumbra (P<0.0001) at 72 h and 7 days after reperfusion, suggesting involvement of monocytes/macrophages in HQL-79-induced expansion of ischemic injury. Our results demonstrated that the neuroprotective effects of HPGDS in our model are mediated by suppression of activation and infiltration of inflammatory cells.

Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Bone Marrow Transplantation; Brain; Chemotaxis, Leukocyte; Disease Models, Animal; Encephalitis; Enzyme Inhibitors; Green Fluorescent Proteins; Hypoxia-Ischemia, Brain; Intramolecular Oxidoreductases; Ischemic Attack, Transient; Isomerases; Lipocalins; Macrophages; Male; Mice; Mice, Inbred C57BL; Microglia; Nerve Tissue Proteins; Neuroprotective Agents; Nitric Oxide Synthase Type II; Piperidines; Reperfusion Injury; Transplantation Chimera

This study investigated cannabinoid receptor-mediated regulation of brain and peripheral cytokines in vivo. The cannabinoid receptor agonist, HU210 attenuated lipopolysaccharide (LPS)-induced increases in IL-1beta and TNFalpha in rat brain and IL-1beta, TNFalpha, IL-6 and IFNgamma in plasma. The CB(1) receptor antagonist, SR141716A, attenuated the immunosupressive effects of HU210 on IL-1beta, but not TNFalpha. SR141716A or the CB(2) receptor antagonist, SR144528, alone attenuated LPS-induced cytokine increases. LPS and/or cannabinoids also reduced circulating lymphocyte numbers and increased corticosterone levels. These data provide evidence for modulation of pro-inflammatory cytokines in vivo by cannabinoid receptors and inform the development of cannabinoids for neuroinflammatory disorders.

Topics: Animals; Camphanes; Corticosterone; Dronabinol; Drug Interactions; Encephalitis; Hypothalamo-Hypophyseal System; Interferon-gamma; Interleukin-10; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Lymphocyte Count; Male; Neuroimmunomodulation; Neuroprotective Agents; Piperidines; Pituitary-Adrenal System; Pyrazoles; Rats; Rats, Sprague-Dawley; Rimonabant; Tumor Necrosis Factor-alpha

Activated glial cells have been implicated in the neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators have been proposed to play a role in glial cell-related brain damage; e.g., free radicals such as nitric oxide (NO), cytokines, and chemokines. Our laboratory has been interested in the effect of psychoactive drugs and their derivatives on the production of these mediators. Cannabinoids have been shown to possess immunomodulatory as well as psychoactive properties. We previously have shown that interleukin (IL)-1beta-stimulated human astrocytes, but not microglia, produce NO. In this study, we investigated the effects of the synthetic cannabinoid WIN55,212-2 on the production of several key inflammatory mediators by human fetal astrocytes activated by IL-1beta. Expression of the cannabinoid receptors CB1 and CB2 was detected on human astrocytes. WIN55,212-2 (10(-5) M) potently inhibited inducible NO synthase (iNOS) and corresponding NO production by IL-1beta-stimulated astrocytes. The CB1 and CB2 receptor-specific antagonists SR141716A and SR144528, respectively, partially blocked this suppressive effect. In addition, treatment of astrocytes with WIN55,212-2 downregulated in a concentration-dependent manner IL-1beta-induced tumor necrosis factor (TNF)-alpha release. Treatment with WIN55,212-2 also inhibited production of the chemokines CXCL10, CCL2 and CCL5 by IL-1beta-activated astrocytes. These findings indicate that WIN55,212-2 inhibits the production of inflammatory mediators by IL-1beta-stimulated human astrocytes and suggest that comparable agents may have therapeutic potential for the management of brain inflammation.

Topics: Astrocytes; Benzoxazines; Camphanes; Cells, Cultured; Chemokines; Down-Regulation; Encephalitis; Gliosis; Humans; Inflammation Mediators; Interleukin-1; Morpholines; Naphthalenes; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Tumor Necrosis Factor-alpha

Topics: Adult; Age Factors; Alcohol Withdrawal Delirium; Basal Ganglia Diseases; Biperiden; Diagnosis, Differential; Encephalitis; Female; Humans; Male; Piperidines; Psychoses, Alcoholic; Seizures

Topics: Child; Diagnosis, Differential; Encephalitis; Gels; Histamine H1 Antagonists; Humans; Male; Piperidines; Psychoses, Substance-Induced

Topics: Child; Delirium; Diagnosis, Differential; Encephalitis; Female; Gels; Histamine H1 Antagonists; Humans; Piperidines; Psychoses, Substance-Induced

Topics: Athetosis; Drug Therapy; Electromyography; Encephalitis; Encephalitis, Arbovirus; Epidemics; Parasympatholytics; Parkinsonian Disorders; Piperidines