Endocannabinoid modulation of TLR4-induced neuroinflammation: implications for autism spectrum disorders
Kerr, Daniel Martin
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Neuroinflammation is a key component of various neurological diseases including Alzheimer's disease, Parkinson's disease, multiple sclerosis and psychiatric and neurodevelopmental disorders such as depression and autism. Accumulating evidence indicates that the endocannabinoid system may play a significant role in modulating immune function and represent an important therapeutic target in the treatment of inflammatory disorders. Thus, one of the main objectives of the work presented in this thesis was to enhance our understanding of the role of the endocannabinoid system in the modulation of peripheral and central acute inflammatory responses in vivo. The data presented herein demonstrated for the first time that systemic administration of URB597, an inhibitor of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for the metabolism of the endocannabinoid anandamide, enhanced N-acylethanolamine levels (including anandamide), an effect associated with an attenuation of the TLR4-induced expression of the pro-inflammatory cytokine IL-1beta in the hypothalamus. In comparison, URB597 did not alter TLR4-induced cytokine or corticosterone levels peripherally, indicating that the anti-inflammatory effect observed in the hypothalamus is centrally mediated. The data presented also demonstrate that systemic administration of JZL184, an inhibitor or the 2-arachidonoyl glycerol catabolising enzyme, monoacylglycerol lipase (MAGL), to rats, inhibits MAGL activity and enhances 2-AG levels peripherally, but not centrally. Despite this, JZL184 attenuated TLR4-induced increases in cytokine expression/levels both peripherally (TNF-alpha and IL-1beta) and in the brain (IL-1beta, IL-6, TNF-alpha and IL-1beta). These data indicate that endocannabinoid modulators such as JZL184 may not need to cross the blood brain barrier to induce potent anti-inflammatory effects centrally. This has important therapeutic implications because such a treatment strategy would avoid the potential psychotropic side effects associated with direct central CB1 receptor activation. The aforementioned studies demonstrate an important role for FAAH and MAGL in modulating neuroinflammatory responses following TLR4 stimulation, thus increasing our knowledge of endocannabinoid-neuroimmune interactions in vivo. Given that endocannabinoids elicit such profound effects on inflammatory processes, a further aim of this work was to characterise immune and endocannabinoid changes in a clinically relevant animal model of autism, the valproic acid (VPA) rat model. Data presented in this thesis demonstrate for the first time that rats prenatally exposed to VPA exhibit increased neuroinflammatory responses, namely enhanced IL-1beta and CCL2 mRNA expression in the cortex, TNF-alpha expression in the hippocampus and GFAP and IL-1beta expression in the cerebellum, following TLR4 stimulation, data correlating with previously published clinical findings. In addition, VPA-exposed rats were found to exhibit alterations in various components of the endocannabinoid system, including reduced expression of the 2-AG synthesising enzyme DAGLalpha in the cerebellum, reduced expression and increased activity of MAGL in the hippocampus, reduced expression of the endocannabinoid targets PPARalpha and GPR55 in the frontal cortex, and reduced expression of PPARalpha and GPR55 in the hippocampus. Thus, VPA-exposed animals exhibit alterations in various aspects of the endocannabinoid system in key brain regions that modulate social and emotional processing. Furthermore, the data presented indicate that VPA-exposed animals display deficits in social behaviour on exposure to a novel conspecific animal, an effect associated with increased levels of anandamide, OEA and PEA in the hippocampus. Increases in N-acylethanolamines in the hippocampus may be a compensatory mechanism in VPA-exposed animals to overcome the stress associated with social exposure. Thus, alterations in neuroinflammatory processes and/or the endocannabinoid system may underlie some of the behavioural abnormalities observed in the VPA model. Endocannabinoid-neuroimmune interactions may provide a novel therapeutic target for some of the symptoms associated with autism. In conclusion, the data presented in this thesis have enhanced our understanding of endocannabinoid modulation of neuroimmune processes, effects which may have important implications for the treatment of a host of neuroinflammatory disorders including autism.