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

Reid, William; Ibrahim, Wael G.; Kim, Saejeong J.; Denaro, Frank; Casas, Rafael; Lee, Dianne E.; Maric, Dragan; Hammoud, Dima A.

doi:10.1016/j.jneuroim.2016.01.022

Cited by 27 publications

(27 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This could lead to D2/D3 deficits that are not fully reflective of dopaminergic loss. This is especially likely in this animal model in which we have consistently shown marked astrocytic loss [12]. In fact, staining in the same group of rats that underwent imaging showed markedly decreased GFAP staining (ratio of Tg/WT= 0.54 +/− 0.18) (Fig.…”

Section: Discussionmentioning

confidence: 73%

“…This implies a complex pre and post synaptic dopaminergic dysfunction in the Tg rats, which we presume is related to chronic neurotoxicity associated with exposure to viral proteins [12, 17, 29, 30]. In the longitudinal component, although decreased [18F]-FP-CMT biding was seen in the WT rats, consistent with age-related degenerative changes, a more marked decrease in binding was noted in the Tg rats, suggesting an additional effect of the transgene, again likely related to chronic exposure to viral proteins.…”

Section: Discussionmentioning

confidence: 99%

“…While decreased [18F]-Fallypride binding in the striatum of the Tg rats compared to age-matched WT rats suggested postsynaptic dopaminergic dysfunction, we suspected that some of the decreased binding could be due to extensive astrocytic loss in this animal model [12] since astrocytes are known to express D2/D3 receptors [19–23]. Therefore, we wanted to confirm dopaminergic dysfunction by concurrently probing the postsynaptic component using [18F]-Fallypride and the presynaptic component using [18F]-FP-CMT, a dopamine transporter (DAT) ligand with good pharmacological selectivity, lack of brain penetrant metabolites and rapid kinetic profile [24].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Dopamine (DA) system dysfunction, observed in both clinical (e.g., Wang et al, 2004;Chang et al, 2008;Kumar et al, 2009;Lee et al, 2014) and preclinical studies (e.g., Webb et al, 2010;Moran et al, 2012;Reid et al, 2016a), may also underlie alterations in spatial learning. Specifically, alterations in the striatal DA system have been reported in pediatric HIV-1 research (Webb et al, 2009;Fitting et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Dose‐dependent neurocognitive deficits following postnatal day 10 HIV‐1 viral protein exposure: Relationship to hippocampal anatomy parameters

Fitting

McLaurin

Booze

et al. 2017

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Despite the availability of antiretroviral prophylactic treatment, pediatric human immunodeficiency virus type 1 (HIV-1) continues to be a significant risk factor in the post-cART era. The time of infection (i.e., during pregnancy, delivery or breastfeeding) may play a role in the development of neurocognitive deficits in pediatric HIV-1. HIV-1 viral protein exposure on postnatal day (P)1, preceding the postnatal brain growth spurt in rats, had deleterious effects on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2008a,b). In the present study, rats were stereotaxically injected with HIV-1 viral proteins, including Tat and gp120, on P10 to further examine the role of timing on neurocognitive development and anatomical parameters of the hippocampus (Fitting et al., 2010). The dose-dependent virotoxin effects observed across development following P10 Tat exposure were specific to spatial learning and absent from prepulse inhibition and locomotor activity. A relationship between alterations in spatial learning and/or memory and hippocampal anatomical parameters was noted. Specifically, the estimated number of neurons and astrocytes in the hilus of the dentate gyrus explained 70% of the variance of search behavior in Morris water maze acquisition training for adolescents and 65% of the variance for adults; a brain-behavior relationship consistent with observations following P1 viral protein exposure. Collectively, late viral protein exposure (P10) results in selective alterations in neurocognitive development without modifying measures of somatic growth, preattentive processing, or locomotor activity, as characterized by early viral protein exposure (P1). Thus, timing may be a critical factor in disease progression, with children infected with HIV earlier in life being more vulnerable to CNS disease.

show abstract

“…This model has been demonstrated to mimic HIV-1–infected patients receiving cART, who have suppressed viral replication (Peng et al 2010). A number of reports have shown abnormal changes in the HIV-1Tg rats, for instance, lower body weight (Peng et al 2010), immune-response alterations (Reid et al 2001), T-cell abnormalities (Reid et al 2004), kidney failure (Ray et al 2003), neurobehavioral and spatial learning and memory changes (Vigorito et al 2007; Lashomb et al 2009; Moran et al 2013), neuronal dysfunction (Reid et al 2016), immunophenotype and cellular response alterations (Abbondanzo and Chang 2014), neurocognitive deficits in pediatric HIV-1 (McLaurin et al 2016, 2017), and gene expression alterations in various brain regions (Li et al 2013). Therefore, this rat is a more suitable animal model, without expensive high-level biosafety demands, for studying the mechanisms of HIV-associated disease in the post-cART era.…”

Section: Animal Models Of Hiv-1 Infection-related Neurodysfunctionmentioning

confidence: 99%

Modulatory Effects of Nicotine on neuroHIV/neuroAIDS

Han

Yang

Chang

et al. 2018

J Neuroimmune Pharmacol

View full text Add to dashboard Cite

Nicotine, one of the key active ingredients in tobacco smoke, exerts its effects via binding to nicotinic acetylcholine receptors (nAChRs). Although both negative and positive pharmacological effects of nicotine have been shown in numerous animals and human studies, its interaction with human immunodeficiency virus-1 (HIV-1) have not been fully elucidated. Even though combined anti-retroviral therapy (cART) limits the progression of HIV-1 to acquired immune deficiency syndrome (AIDS), HIV-associated neurocognitive disorders (HAND) remain prevalent. There is thus a compelling need to enhance our understanding of HAND-related neurologic dysfunction. Some biochemical pathways and physiological dysfunctions have been found to be shared by HAND and Alzheimer's (AD) or Parkinson's (PD) diseases, and nicotine may exert the same neuroprotection in HAND that has been observed in both AD and PD. In the past dozen years, various potential therapeutic effects of nicotine such as neuroprotection have been revealed in both in vivo and in vitro studies, including using HIV-1 transgenic (HIV-1Tg) rat model, which mimics HIV-infected patients receiving cART. In the current review, we describe recent progress in the prevalence of HIV/AIDS with and without cigarette smoking, some animal models for studying neural dysfunction associated with HIV-1 infection, elucidating the modulatory effects of cigarette smoking/nicotine on HIV/AIDS, the anti-inflammatory effects of nicotine, and the neuroprotective effects observed in HIV-1Tg rat model. Taken together, these findings suggest the following: although tobacco smoking does cause deleterious effects in both health and disease conditions such as HIV infection, nicotine, the significant component of tobacco smoke, has been shown to possess some neuroprotective effects in HIV patients, possible via its anti-inflammatory activities. It is therefore necessary to study nicotine's dual effects on neuroHIV/neuroAIDS in hope of better defining the potential medical uses of nicotine or its analogues, and to make them available in a purer and less dangerous form.

show abstract

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

Cited by 27 publications

References 80 publications

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

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

Dose‐dependent neurocognitive deficits following postnatal day 10 HIV‐1 viral protein exposure: Relationship to hippocampal anatomy parameters

Modulatory Effects of Nicotine on neuroHIV/neuroAIDS

Contact Info

Product

Resources

About