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

• Published in: Brain, behavior, and immunity behavior, and immunity, 2019-02, Vol.76, p.e34-e35
• Main Authors: Kwilasz, A.J., Todd, L.S., Duran-Malle, L.C., Schrama, A.E., Mitten, E.H., Dam, A.M. Van, Maier, S.F., Rice, K.C., Watkins, L.R., Barrientos, R.M.
• Format: Article
• Language: English
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2018.11.282

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-1β (IL-1β) 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-1β 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.