Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI

Murphy, Aniella; Kelschenbach, Jennifer; He, Hongqing; Chao, Wei; Kim, Boe-Hyun; Volsky, David J.; Berman, Joan W.

doi:10.3389/fimmu.2022.1004985

Cited by 12 publications

(10 citation statements)

References 85 publications

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“…5 ), suggest that cells resident in the brain, likely perivascular macrophages and microglia, maintain EcoHIV infection and its pathogenic effects upon cognitive function regardless of potential loss of CCL2 driven monocyte migration to the brain. A collaborative group including some of the coauthors of the present work recently reported that NCI is reversed by treatment of EcoHIV-infected mice with buprenorphine 56 . Buprenorphine treatment also reduced HIV burdens and inflammatory monocyte levels in the brain 56 , suggesting that continuing migration of HIV-infected monocytes to the brain is required to maintain HIV-NCI.…”

Section: Discussionmentioning

confidence: 64%

“…A collaborative group including some of the coauthors of the present work recently reported that NCI is reversed by treatment of EcoHIV-infected mice with buprenorphine 56 . Buprenorphine treatment also reduced HIV burdens and inflammatory monocyte levels in the brain 56 , suggesting that continuing migration of HIV-infected monocytes to the brain is required to maintain HIV-NCI. However, since buprenorphine also affects various aspects of behavior 57 , 58 , additional mechanisms may apply.…”

Section: Discussionmentioning

confidence: 64%

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CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

Kelschenbach

et al. 2023

Sci Rep

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HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but the roles of CCL2 in established NCI are not fully defined. We addressed this question during infection of conventional and CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. EcoHIV enters mouse brain within 5 days of infection, but NCI develops gradually with established cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI and reduced macrophage infection. In contrast, bindarit treatment of mice 4 weeks after infection affected neither brain virus burden nor NCI. Based on these findings we propose that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. These findings suggest that NCI therapy must act within the brain.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 64%

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

Kelschenbach

et al. 2023

Sci Rep

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“…EcoHIV NCI in mice 54 ; possibly through its action on CCL2 expression 38 . This suggests that buprenorphine reverses NCI through inhibition of monocyte migration, however, buprenorphine also has effects within the brain upon various aspects of behavior 55,56 , so the mechanism of buprenorphine action upon EcoHIV NCI remains under study.…”

Section: Discussionmentioning

confidence: 99%

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

Kelschenbach

et al. 2023

Preprint

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HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but direct demonstration of the role of CCL2 in NCI pathogenesis in vivo is lacking. We addressed this question during infection of conventional or CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. NCI develops gradually during EcoHIV infection of mice, with chronic cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI, and reduced macrophage infection. In contrast, bindarit treatment of mice four weeks after infection affected neither brain virus burden nor NCI, suggesting that once established, brain disease was independent of CCL2. Our results indicate that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. A conclusion from these findings is that NCI therapy must act within the brain. .

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“…A reduced brain monocyte-induced inflammatory response and reversal of the dendritic injury to the hippocampus and cortex due to buprenorphine might also explain the improvement. Animal studies reported that buprenorphine pretreatment prevents HIV-induced cognitive impairment in mice, and buprenorphine treatment of HIV-NCI (HIV-associated neurocognitive disorder) mice reverses the disease 44,45 . Our patients were on relatively low-dose buprenorphine (7.07 ± 2.92 mg daily).…”

Section: Discussionmentioning

confidence: 95%

“…Animal studies reported that buprenorphine pretreatment prevents HIV-induced cognitive impairment in mice, and buprenorphine treatment of HIV-NCI (HIV-associated neurocognitive disorder) mice reverses the disease. 44,45 Our patients were on relatively low-dose buprenorphine (7.07 ± 2.92 mg daily). Pre-experimental studies showed that low-dose buprenorphine might induce the expression of oligodendrocytes and myelination, further improving plasticity and remodeling.…”

Section: Discussionmentioning

confidence: 99%

Neurocognitive Functions After 6-Month Buprenorphine (Naloxone)–Based Opioid Agonist Maintenance Treatment

Ghosh,

Shaktan,

Nehra

et al. 2024

J Clin Psychopharmacol

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Background Medications for opioid use disorder (OUD) may influence neurocognitive functions. Inadequate power, confounders, and practice effects limit the validity of the existing research. We examined the change in cognitive functions in patients with OUD at 6-month buprenorphine (naloxone) posttreatment and compared the cognitive performance of the buprenorphine-treated group with control subjects. Methods We recruited 498 patients with OUD within a week of initiating buprenorphine. Assessments were done twice—at baseline and 6 months. Those abstinent from illicit opioids and adherent to treatment (n = 199) underwent follow-up assessments. Ninety-eight non–substance-using control subjects were recruited from the community. The neurocognitive assessments comprised the Wisconsin Card Sorting Test, Iowa Gambling Task, Trail-Making Tests A and B (TMT-A and TMT-B), and verbal and visual N-Back Test. We controlled for potential effect modifiers. Results Twenty-five of the 32 test parameters significantly improved with 6 months of buprenorphine treatment; 20 parameters withstood corrections for multiple comparisons (P < 0.001). The improved test domains spread across cognitive tests: Wisconsin Card Sorting Test (perseverative errors and response, categories completed, conceptual responses), TMTs (time to complete), verbal and visual N-Back Tests (hits, omission, and total errors). After treatment, OUD (vs control subjects) had less perseverative response and error (P < 0.001) and higher conceptual response (P = 0.004) and took lesser time to complete TMT-A (P < 0.001) and TMT-B (P = 0.005). The baseline neurocognitive functions did not differ between those who retained and those who discontinued the treatment. Conclusion Cognitive functions improve in patients with OUD on buprenorphine. This improvement is unlikely to be accounted for by the practice effect, selective attrition, and potential confounders.

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Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI

Cited by 12 publications

References 85 publications

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Neurocognitive Functions After 6-Month Buprenorphine (Naloxone)–Based Opioid Agonist Maintenance Treatment

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