Abstract # 3170 The TLR2/4 antagonist (+)-naltrexone blocks contextual long-term memory deficits in experimental autoimmune encephalitis and associated neuroinflammation in hippocampus

Approximately half of individuals suffering from multiple sclerosis (MS) express cognitive deficits in the form of memory impairments. Previously we have shown that administration of toll-like 2/4 (TLR2/4) antagonists such as (+)-naltrexone [(+)-NTX] block neuropathic pain and associated spinal inflammation in rats. In this study, we examined the effects of (+)-NTX on memory impairments and associated brain inflammation in a rat model of MS, experimental autoimmune encephalomyelitis (EAE). Male Dark Agouti rats were induced with EAE and 14 days later received subcutaneous (+)-NTX or saline for 14 days. Contextual- and auditory-fear conditioning were then conducted to assess memory impairments one week after beginning (+)-NTX administration. We found that EAE induced impairments in long-term contextual fear memory but not short-term contextual- or auditory-related fear memory. This effect was associated with increased interleukin-1 β (IL-1 β ) mRNA expression in the hippocampus but not the amygdala. Importantly, (+)-NTX blocked EAE-induced impairments in long-term contextual fear memory and the associated increased hippocampal IL-1 β expression. Moreover, (+)-NTX blocked hippocampal expression of TLR2, TLR4, NLRP3, and IL-17 mRNA, suggesting blockade of the TLR2/4, NLRP3 inflammasome and Th17 cell signaling as additional mechanisms by which (+)-NTX exerts its therapeutic effects. These findings support the role of TLR2/4 antagonists as potential treatments for MS-related cognitive deficits and encourage future research on TLR2/4 antagonists as treatments for various symptoms associated with inflammatory-related diseases, including MS.