Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone

Autor: Tracey A Larson, Eric H. Mitten, Madison A. Clements, Ruth M. Barrientos, Linda R. Watkins, Scott T. Litwiler, Kevin M. Harris, Andrew J. Kwilasz, Julissa Chante Duran-Malle, Kenner C. Rice, Xiaohui Wang, Anouk E.W. Schrama, Steven F. Maier, Laurel S. Todd, Anne Marie van Dam
Přispěvatelé: Anatomy and neurosciences, AMS - Ageing & Vitality, AMS - Tissue Function & Regeneration, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Kwilasz, A J, Todd, L S, Duran-Malle, J C, Schrama, A E W, Mitten, E H, Larson, T A, Clements, M A, Harris, K M, Litwiler, S T, Wang, X, Van Dam, A M, Maier, S F, Rice, K C, Watkins, L R & Barrientos, R M 2021, ' Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone ', Behavioural Brain Research, vol. 396, 112896 . https://doi.org/10.1016/j.bbr.2020.112896
Behavioural Brain Research, 396:112896. Elsevier
Behav Brain Res
ISSN: 0166-4328
DOI: 10.1016/j.bbr.2020.112896
Popis: Multiple sclerosis (MS) is associated with burdensome memory impairments and preclinical literature suggests that these impairments are linked to neuroinflammation. Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. Here we extend these findings to first demonstrate that (+)-NTX blocks TLR2 in addition to TLR4. Additionally, we examined in two rat strains whether (+)-NTX could attenuate learning and memory disturbances and associated neuroinflammation using a low-dose experimental autoimmune encephalomyelitis (EAE) model of MS. EAE is the most commonly used experimental model for the human inflammatory demyelinating disease, MS. This low-dose model avoided motor impairments that would confound learning and memory measurements. Fourteen days later, daily subcutaneous (+)-NTX or saline injections began and continued throughout the study. Contextual and auditory-fear conditioning were conducted at day 21 to assess hippocampal and amygdalar function. With this low-dose model, EAE impaired long-term, but not short-term, contextual fear memory; both long-term and short-term auditory-cued fear memory were spared. This was associated with increased mRNA for hippocampal interleukin-1β (IL-1β), TLR2, TLR4, NLRP3, and IL-17 and elevated expression of the microglial marker Iba1 in CA1 and DG regions of the hippocampus, confirming the neuroinflammation observed in higher-dose EAE models. Importantly, (+)-NTX completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects. These findings suggest that (+)-NTX may exert therapeutic effects on memory function by dampening the neuroinflammatory response in the hippocampus through blockade of TLR2/TLR4. This study suggests that TLR2 and TLR4 antagonists may be effective at treating MS-related memory deficits.
Databáze: OpenAIRE
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