دورية أكاديمية
Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat.
| العنوان: | Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat. |
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| المؤلفون: | League AF; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States., Gorman BL; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States., Hermes DJ; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States., Johnson CT; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States., Jacobs IR; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States., Yadav-Samudrala BJ; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States., Poklis JL; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States., Niphakis MJ; Department of Chemistry, Scripps Research Institute, La Jolla, CA, United States., Cravatt BF; Department of Chemistry, Scripps Research Institute, La Jolla, CA, United States., Lichtman AH; Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States., Ignatowska-Jankowska BM; Okinawa Institute of Science and Technology, Neuronal Rhythms in Movement Unit, Okinawa, Japan., Fitting S; Department of Psychology and Neuroscience, University of North Carolina Chapel Hill, Chapel Hill, NC, United States. |
| المصدر: | Frontiers in neurology [Front Neurol] 2021 Aug 16; Vol. 12, pp. 651272. Date of Electronic Publication: 2021 Aug 16 (Print Publication: 2021). |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101546899 Publication Model: eCollection Cited Medium: Print ISSN: 1664-2295 (Print) Linking ISSN: 16642295 NLM ISO Abbreviation: Front Neurol Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation, 2010]- |
| مستخلص: | While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic MJN110 administration in vivo increased 2-AG levels in the prefrontal cortex (PFC) and striatum across Tat(+) and Tat(-) groups and restored PFC N-arachidonoylethanolamine (AEA) levels in Tat(+) subjects. While Tat expression significantly increased rate of reward-related behavioral task acquisition in a novel discriminative stimulus learning and cognitive flexibility assay, MJN110 altered reversal acquisition specifically in Tat(+) mice to rates indistinguishable from Tat(-) controls. Collectively, our results suggest a neuroprotective role of MAGL inhibition in reducing neuronal hyperexcitability, restoring dendritic arborization complexity, and mitigating neurocognitive alterations driven by viral proteins associated with latent HIV-1 infection. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 League, Gorman, Hermes, Johnson, Jacobs, Yadav-Samudrala, Poklis, Niphakis, Cravatt, Lichtman, Ignatowska-Jankowska and Fitting.) |
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| معلومات مُعتمدة: | P30 DA033934 United States DA NIDA NIH HHS; R21 DA041903 United States DA NIDA NIH HHS; R01 DA039942 United States DA NIDA NIH HHS; T32 DA007244 United States DA NIDA NIH HHS; R01 DA045596 United States DA NIDA NIH HHS |
| فهرسة مساهمة: | Keywords: 2-arachidonoyl glycerol; HIV; MJN110; Tat; endocannabinoids; excitotoxicity; monoacylglycerol lipase |
| تواريخ الأحداث: | Date Created: 20210906 Latest Revision: 20220309 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8415271 |
| DOI: | 10.3389/fneur.2021.651272 |
| PMID: | 34484091 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1664-2295 |
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| DOI: | 10.3389/fneur.2021.651272 |