Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

Wayman, Wesley N.; Chen, Lihua; Persons, Amanda L.; Napier, T. Celeste

doi:10.2174/0929867322666150311164504

Cited by 20 publications

(19 citation statements)

References 96 publications

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“…In view of what seems like a less prominent role for microglial activation in this model, we concur with previous studies asserting prolonged exposure to viral proteins as the main cause of neuropathology in the Tg rat (Midde, Gomez, 2011, Peng, Vigorito, 2010, Royal, Zhang, 2012, Vigorito, Connaghan, 2015, Wayman, Chen, 2015). Interestingly, we were able to detect serum gp120 in older but not in younger rats.…”

Section: Discussionsupporting

confidence: 92%

“…This however can be explained by the inherent differences between the two animal models as far as pathophysiology: the HIV humanized mouse is an immunodeficient model (NOD/scid-IL-2Rgamma(c)(null) mice) reconstituted with human hematopoietic CD34(+) stem cells and infected with HIV, thus reflecting human HIV-1 infection more closely, with persistent viremia, profound CD4+ T lymphocyte loss and infection of human monocyte-macrophages in the meninges/perivascular spaces of the rodent brain (Boska, Dash, 2014, Epstein, Narayanasamy, 2013). The Tg rat on the other hand reflects chronic viral protein toxicity (Midde et al, 2011, Peng, Vigorito, 2010, Royal, Zhang, 2012, Vigorito et al, 2015, Wayman et al, 2015), and is closer pathologically to optimally-treated HIV+ patients than actively infected patients, as described below.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of neuropathology in the HIV-1 transgenic rat at different ages

Reid

Ibrahim

Kim

et al. 2016

Journal of Neuroimmunology

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The transgenic HIV-1 rat (Tg) is a commonly used neuroHIV model with documented neurologic/behavioral deficits. Using immunofluorescent staining of the Tg brain, we found astrocytic dysfunction/damage, as well as dopaminergic neuronal loss/dysfunction, both of which worsening significantly in the striatum with age. We saw mild microglial activation in young Tg brains, but this decreased with age. There were no differences in neurogenesis potential suggesting a neurodegenerative rather than a neurodevelopmental process. Gp120 CSF levels exceeded serum gp120 levels in some animals, suggesting local viral protein production in the brain. Further probing of the pathophysiology underlying astrocytic injury in this model is warranted.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

Reid

Ibrahim

Kim

et al. 2016

Journal of Neuroimmunology

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“…In another study, gp120 produced loss of nigrostriatal neurons, as shown both by histochemical analysis of brain sections for apoptosis and biochemical determination of dopamine concentration [33]. In the Tg rat, previous papers asserted prolonged exposure to viral proteins as the main cause of neuropathology [17, 18, 29, 34, 35], with dopaminergic system dysfunction being a characteristic finding in neurobehavioral studies [10, 11, 13]. We have previously shown expression of viral proteins in the brain, CSF and serum of the Tg rats, which could potentially explain the dopaminergic neuronal toxicity we identified by PET.…”

Section: Discussionmentioning

confidence: 99%

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV

Sinharay

Lee

Shah

et al. 2017

Nuclear Medicine and Biology

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Introduction In vivo imaging biomarkers of various HIV neuropathologies, including dopaminergic dysfunction, are still lacking. Towards developing dopaminergic biomarkers of brain involvement in HIV, we assessed the pre and postsynaptic components of the dopaminergic system in the HIV-1 transgenic rat (Tg), a well-characterized model of treated HIV+ patients, using small-animal PET imaging. Methods 15–18 month-old Tg and wild type (WT) rats were imaged with both [18F]-FP-CMT, a dopamine transporter (DAT) ligand (n=16), and [18F]-Fallypride, a D2/D3 dopamine receptor (D2/D3DR) ligand (n=16). 5–8 month-old Tg and WT rats (n=18) were also imaged with [18F]-FP-CMT. A subset of animals was imaged longitudinally at 7 and 17 months of age. Multiplex immunohistochemistry staining for DAT, tyrosine hydroxylase, D2DR, D3DR, GFAP, Iba1 and NeuN was performed on a subgroup of the scanned animals. Results [18F]-FP-CMT and [18F]-Fallypride binding potential (BPND) values were significantly lower in 15–18 month-old Tg compared to age-matched WT rats (p< 0.0001 and 0.001, respectively). [18F]-FP-CMT BPND values in 5–8 month-old rats, however, were not significantly different. Longitudinal age-related decrease in [18F]-FP-CMT BPND was exacerbated in the Tg rat. Immunohistochemistry showed decreased staining of dopaminergic markers in Tg rats. Rats with higher serum gp120 had lower mean BPND values for both ligands. Conclusions We found presynaptic and postsynaptic dopaminergic dysfunction/loss in older Tg compared to WT rats. We believe this to be related to neurotoxicity of viral proteins present in the Tg rats’ serum and brain. Advances in Knowledge Our findings confirm prior reports of neurobehavioral abnormalities suggestive of dopaminergic dysfunction in this model. They also suggest similarities between the Tg rat and HIV+ patients as far as dopaminergic dysfunction. Implications for patient Care The Tg rat, along with the above-described quantitative PET imaging biomarkers, can have a role in the evaluation of HIV neuroprotective therapies prior to human translation.

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“…In this regard, HIV-1 Tat was found to trigger mitochondrial depolarization (Régulier et al, 2004; Lecoeur et al, 2012) and increased intracellular generation of reactive oxygen species (ROS) resulting in neuronal degeneration in primary cultures of rat hippocampal rat cells (Aksenov et al, 2006). Previous studies reported the combined action of cocaine exposure and Tat released from infected glial are neurotoxic in the CNS (Wayman et al, 2015). In line with these findings, our results show that treating rat hippocampal neurons with either cocaine alone or in combination with HIV-1 Tat, strongly decreased mitochondrial ATP production.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Tat and Cocaine Impair Survival of Cultured Primary Neuronal Cells via a Mitochondrial Pathway

Simone

Darbinian

Amini

et al. 2016

J Neuroimmune Pharmacol

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Addictive stimulant drugs, such as cocaine, are known to increase the risk of exposure to HIV-1 infection and hence predispose towards the development of AIDS. Previous findings suggested that the combined effect of chronic cocaine administration and HIV-1 infection enhances cell death. Neuronal survival is highly dependent on the health of mitochondria providing a rationale for assessing mitochondrial integrity and functionality following cocaine treatment, either alone or in combination with the HIV-1 viral protein Tat, by monitoring ATP release and mitochondrial membrane potential (ΔΨm). Our results indicate that exposing human and rat primary hippocampal neurons to cocaine and HIV-1 Tat synergistically decreased both mitochondrial membrane potential and ATP production. Additionally, since previous studies suggested HIV-1 infection alters autophagy in the CNS, we investigated how HIV-1 Tat and cocaine affect autophagy in neurons. The results indicated that Tat induces an increase in LC3-II levels and the formation of Parkin-ring-like structures surrounding damaged mitochondria, indicating the possible involvement of the Parkin/PINK1/DJ-1 (PPD) complex in neuronal degeneration. The importance of mitochondrial damage is also indicated by reductions in mitochondrial membrane potential and ATP content induced by HIV-1 Tat and cocaine.

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Cortical Consequences of HIV-1 Tat Exposure in Rats are Enhanced by Chronic Cocaine

Cited by 20 publications

References 96 publications

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

Characterization of neuropathology in the HIV-1 transgenic rat at different ages

Cross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV

HIV-1 Tat and Cocaine Impair Survival of Cultured Primary Neuronal Cells via a Mitochondrial Pathway

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