Opioid and chemokine regulation of cortical synaptodendritic damage in HIV-associated neurocognitive disorders

Nash, Bradley; Festa, Lindsay; Lin, Chih-Yang; Meucci, Olimpia

doi:10.1016/j.brainres.2019.146409

Cited by 13 publications

(10 citation statements)

References 172 publications

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“…Neuropathology studies are currently necessary to confirm synaptodendritic damage and neuronal alterations in relevant brain regions. Unfortunately, most published neuropathology studies on HAND are from the pre-ART era or use clinical samples from patients with acquired immunodeficiency syndrome (AIDS), suggesting that they are not completely reflective of the current pathology [ 37 ]. Therefore, new studies using tissues from ART-treated patients with controlled infection are urgently needed.…”

Section: Neuroimaging and Neuropathological Studies In Hand Patientsmentioning

confidence: 99%

“…As predicted for highly plastic spines, the density of mature thin spines is more strongly associated with cognitive flexibility than any other spine type [ 84 ]. Furthermore, HIV-transgenic rats show dendritic spine and branching deficits in layer II/III neurons of the motor cortex, including an increased percentage of filopodia [ 37 ], suggesting that this could correlate with motor dysfunction. Another study examined synaptodendritic injury in older female and male HIV-transgenic rats and reported thin spine deficits and increased stubby spine density on similar regions of proximal dendrites, although neurocognitive impairment later in disease progression predominantly affected male rats [ 91 ].…”

Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

“…Indeed, past studies showed that a single injection of gp120 elicited long-term damage. Specifically, intracerebroventricular injection of gp120 IIIB in adult male rats decreases dendritic spine density in several cortical regions, including the medial prefrontal cortex [ 90 ] and the motor cortex [ 37 ]. As spine loss in the prefrontal cortex correlated with decreased cognitive flexibility in the same rats, it is possible that gp120-induced spine loss in the motor cortex could contribute to motor deficits.…”

Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

“…A balance between synaptic actin polymerization and depolymerization regulates their morphology and maintenance [ 160 ] . These processes are often disrupted in neurologic disorders, including HAND [ 37 , 161 ]. Recent studies in animal models have shown that spine alterations in the prefrontal cortex of male HIV-transgenic rats involve an actin depolymerization pathway regulated by the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1) [ 84 ].…”

Section: Mechanisms That Affect Synaptodendritic Damage and Network Dysfunction In Handmentioning

confidence: 99%

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Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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HIV-associated neurocognitive disorder (HAND) is characterized by cognitive and behavioral deficits in people living with HIV. HAND is still common in patients that take antiretroviral therapies, although they tend to present with less severe symptoms. The continued prevalence of HAND in treated patients is a major therapeutic challenge, as even minor cognitive impairment decreases patient’s quality of life. Therefore, modern HAND research aims to broaden our understanding of the mechanisms that drive cognitive impairment in people with HIV and identify promising molecular pathways and targets that could be exploited therapeutically. Recent studies suggest that HAND in treated patients is at least partially induced by subtle synaptodendritic damage and disruption of neuronal networks in brain areas that mediate learning, memory, and executive functions. Although the causes of subtle neuronal dysfunction are varied, reversing synaptodendritic damage in animal models restores cognitive function and thus highlights a promising therapeutic approach. In this review, we examine evidence of synaptodendritic damage and disrupted neuronal connectivity in HAND from clinical neuroimaging and neuropathology studies and discuss studies in HAND models that define structural and functional impairment of neurotransmission. Then, we report molecular pathways, mechanisms, and comorbidities involved in this neuronal dysfunction, discuss new approaches to reverse neuronal damage, and highlight current gaps in knowledge. Continued research on the manifestation and mechanisms of synaptic injury and network dysfunction in HAND patients and experimental models will be critical if we are to develop safe and effective therapies that reverse subtle neuropathology and cognitive impairment.

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Section: Neuroimaging and Neuropathological Studies In Hand Patientsmentioning

confidence: 99%

Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

Section: Synapodendritic Damage and Neuronal Activity Changes In Hand Experimental Modelsmentioning

confidence: 99%

Section: Mechanisms That Affect Synaptodendritic Damage and Network Dysfunction In Handmentioning

confidence: 99%

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Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

Irollo

Luchetta

et al. 2021

Cell. Mol. Life Sci.

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“…HIV-infected and activated cells also facilitate recruitment of additional monocytes into the CNS, establishing and propagating chronic neuroinflammation (34, 49–51). While neurons do not become infected with HIV, they are impacted by viral proteins, cytokines, and neurotoxins, all of which contribute to neuronal damage and loss and the development of neurocognitive impairment (48, 52–54). Table 1 summarizes the effects of opioids and ART on the various cell types that contribute to HIV neuropathogenesis.…”

Section: Effects Of Opioids On Molecular Mechanisms That Mediate Hiv mentioning

confidence: 99%

The Effects of Opioids on HIV Neuropathogenesis

et al. 2019

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HIV associated neurocognitive disorders (HAND) are a group of neurological deficits that affect approximately half of people living with HIV (PLWH) despite effective antiretroviral therapy (ART). There are currently no reliable molecular biomarkers or treatments for HAND. Given the national opioid epidemic, as well as illegal and prescription use of opioid drugs among PLWH, it is critical to characterize the molecular interactions between HIV and opioids in cells of the CNS. It is also important to study the role of opioid substitution therapies in the context of HIV and CNS damage in vitro and in vivo. A major mechanism contributing to HIV neuropathogenesis is chronic, low-level inflammation in the CNS. HIV enters the brain within 4–8 days after peripheral infection and establishes CNS reservoirs, even in the context of ART, that are difficult to identify and eliminate. Infected cells, including monocytes, macrophages, and microglia, produce chemokines, cytokines, neurotoxic mediators, and viral proteins that contribute to chronic inflammation and ongoing neuronal damage. Opioids have been shown to impact these immune cells through a variety of molecular mechanisms, including opioid receptor binding and cross desensitization with chemokine receptors. The effects of opioid use on cognitive outcomes in individuals with HAND in clinical studies is variable, and thus multiple biological mechanisms are likely to contribute to the complex relationship between opioids and HIV in the CNS. In this review, we will examine what is known about both HIV and opioid mediated neuropathogenesis, and discuss key molecular processes that may be impacted by HIV and opioids in the context of neuroinflammation and CNS damage. We will also assess what is known about the effects of ART on these processes, and highlight areas of study that should be addressed in the context of ART.

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