NeuroImmune pharmacology and therapeutics最新文献

Objective: HIV-1 infection affects approximately 38.4 million people around the world. The advent of combination anti-retroviral therapy (cART) has greatly improved the quality of life of infected individuals; however, roughly 50 % of these individuals will still experience HIV-1-associated neurocognitive disorders (HAND). Additionally, the gastrointestinal microbiome has been reported to be dysbiotic in HIV-1 infected individuals, regardless of adherence to cART. Current research has pointed to the gut-brain-microbiota axis as a potential target to treat both cognitive deficits and microbial changes. The present study investigated S-Equol (SE) as a potential therapeutic for HAND by modulating the gastrointestinal microbiome.

Methods: The study included 21 HIV-1 Tg rats and 21 F344 control animals to test the effect 0.2 mg SE has on cocaine-maintained responding on a PR schedule of reinforcement.

Results: Gastrointestinal microbiome alterations between genotypes were found at the phylum and genus level, regardless of treatment group, and SE treatment had both main effects and interactions with genotype. Prevotella_UCG_001 was significantly associated with lever presses for drug, suggesting an effect on motivation for cocaine. Alloprevotella was found to significantly differentiate between genotype by treatment effects, indicating that SE differently affects genotypes.

Conclusions: SE may provide a novel adjuvant treatment in addition to cART for HIV-1-associated dysbiosis and associated neurocognitive dysfunction.

Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.

Objectives: Opioid use during pregnancy is associated with adverse perinatal outcomes, but its effects on placental biology are not well understood. Because the placenta plays a vital role in fetal development and immune regulation, we examined how maternal opioid exposure influences microbial DNA signatures and immune gene expression in the placenta.

Methods: Placentas from opioid-exposed and control C57 BL/6 female mice were analyzed through 16S rRNA gene sequencing, bulk RNA sequencing and pathway enrichment analysis.

Results: Opioid-exposed placentas showed altered microbial DNA profiles, including increased α-diversity and enrichment of Staphylococcus spp. Transcriptomic analysis revealed 357 differentially expressed genes, emphasizing immune pathways, including dendritic cell-NK cell crosstalk, immunogenic cell death, and cytokine storm signaling. STAT3 signaling and heparan sulfate biosynthesis were downregulated. Pathways related to apoptosis, cytotoxicity, and neonatal death were upregulated.

Conclusions: Maternal opioid exposure may disrupt placental microbial and immune environments, potentially leading to structural compromise through immune-mediated cellular apoptosis.

Currently, no US Food and Drug Administration-approved treatments exist to manage HIV-associated sensory neuropathy (HIV-SN) and management is largely confined to adjusting antiretroviral therapy (ART) doses and medications. Thus, this urgent health crisis requires strong research commitment to identify a cure or palliative treatment. This review explores the current state-of-the-art related to HIV-SN. It first explores recent developments in the understanding of HIV-SN, emphasizing the importance of developments in the HIV-SN mouse model and non-myelination intra epidermal never fiber denervation. Next, the neurotoxic side effects of ART are summarized. Finally, we explore the interactions and synergy between HIV-SN and ART in the pathogenesis of peripheral neuropathy. While the overall mortality related to HIV has decreased significantly in recent decades, further elucidation of the exact mechanisms of HIV-SN is needed to better treat patients living with HIV as a chronic condition.

Objectives: We aimed to cross-sectionally and longitudinally compare brain morphometry and neuropsychiatric symptoms, and evaluate their relationship, in participants with Post-Coronavirus Disease Condition (PCC) and healthy Controls.

Methods: At Baseline, 29 PCC (19 female; average age=42.4±12.2 years; 242±156 days since infection) and 25 Controls (14 female; 44.1±12.3 years) completed the NIH Toolbox Emotion, Motor and Cognition Batteries; Patient Reported Outcomes Measurement Information System (PROMIS); and structural brain MRI (thickness, areas, volumes). We compared neurobehavioral performance on the NIH Toolbox and PROMIS and structural brain morphometry for 34 cortical regions and 8 subcortical volumes, between PCC and matched Controls at Baseline (~8 months post-infection) and 11 PCC and 7 Controls at a Follow-Up Visit (~3 years post-infection).

Results: At Baseline, PCC had significantly larger putamen and amygdala (FDR-corrected p=0.04; +5.3 and 5.9%) and a trend for larger hippocampus and accumbens (uncorrected-p=0.012 and 0.027, +5.1 and 12.9%) than Controls. PCC also tended to have 4 thicker cortices (p=0.010-0.049; +3.6-6.5%), 6 larger surface areas (p=0.009-0.023; +5.9-8.6%), and 9 larger cortical volumes (p=0.003-0.008; +4.2-10.7%). These abnormal measures were associated with more anxiety, depression, and pain (r=0.5-0.75; p=0.005-0.04). At Follow-Up, PCC had more sadness, fear, pain, and fatigue compared to Controls. However, group differences in morphometry diminished and PCC neurobehavioral performance tended to improve.

Conclusions: Structural abnormalities in PCC suggest compensatory processes such as enhanced myelination or neurogenesis, rather than neuroinflammation, which in turn may contribute to persistent neurobehavioral symptoms. However, these alterations and symptoms may improve three years after infection.

On June 8, 2025, the 29th Scientific Conference of the Society on NeuroImmune Pharmacology (SNIP) hosted a workshop on the Creation, Care, and Translation of Humanized Mouse for HIV/AIDS Research. The workshop was convened by the society officers Drs. Howard E. Gendelman and Santhi Gorantla. A series of four presentations provided details about the generation, care and use of humanized mouse models. The presentation titles and presenters were: (i) "Next-Generation Humanized Mouse Models of HIV/AIDS Research" by Dr. Angela Wahl; (ii) "Advancing Humanized Mice Research Through Shared Resources" by Dr. Jennifer Koblinski; (iii) "NeuroHIV Humanized Mouse Models" by Dr. Santhi Gorantla; and (iv) "Studies on HIV Evolution, Latency, and Elite Control in Humanized Mice" by Dr. Ramesh Akkina. The presentations were followed by a discussion with workshop participants led by Dr. Paul W. Denton. Presentation summaries are provided in this report and are followed by questions offered by workshop participants alongside panel responses.

Objecives: Approximately 80 % of people living with HIV (PLWH) develop chronic pain and preclinical studies support the involvement of the HIV-1 regulatory protein, trans-activator of transcription (Tat). Phytocannabinoids may attenuate pain in PLWH; however, these data are controversial, and the biological mechanisms are difficult to untangle from psychosocial factors in people.

Methods: We have examined the therapeutic capacity of minor phytocannabinoids to attenuate Tat-promoted visceral hyperalgesia (acetic acid writhing assay) and reflexive nociception (warm water tail flick assay) in transgenic mice. We hypothesized that conditional expression of Tat_1-86 in male and female mice [Tat(+) mice] would amplify pain responses compared to controls [Tat(-) mice], and that phytocannabinoids could ameliorate these effects.

Results: Irrespective of sex, Tat(+) mice demonstrated greater visceral pain responses than did Tat(-) controls. The phytocannabinoids, cannabigerolic acid (CBGA), cannabidiol (CBD), and cannabinol (CBN), attenuated Tat-induced visceral pain in both males and females. However, the effectiveness of these cannabinoids varied by sex with CBN being more efficacious in males, while cannabigerol (CBG) alleviated visceral pain only in Tat(+) females. Cannabidiolic acid (CBDA) and cannabidivarin (CBDV) were not effective in either sex. CBGA and CBG were also efficacious in the tail flick test among Tat(-) males and females, but demonstrated only small, sex-dependent effects to reverse Tat-induced nociception. CBD and CBN exerted little-to-no efficacy in this test.

Conclusions: These data suggest that phytocannabinoids exert analgesia for HIV-related pain, potentially aiding in the development of personalized pain management strategies.

Diagnostic criteria for substance use disorder, cocaine type (i.e., cocaine use disorder), outlined in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, imply that the disorder arises, at least in part, from the maladaptive allocation of behavior to drug use. To date, however, the neural circuits involved in the allocation of behavior have not been systematically evaluated. Herein, a chemogenetics approach (i.e., designer receptors exclusively activated by designer drugs (DREADDs)) was utilized in combination with a concurrent choice self-administration experimental paradigm to evaluate the role of the mesolimbic neurocircuit in the allocation of behavior. Pharmacological activation of hM3D(G_q) DREADDs in neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (AcbSh) induced a sex-dependent shift in the allocation of behavior in rodents transduced with DREADDs. Specifically, male DREADDs animals exhibited a robust increase in responding for a natural (i.e., sucrose) reward following pharmacological activation of the VTA-AcbSh circuit; female DREADDs rodents, in sharp contrast, displayed a prominent decrease in drug-reinforced (i.e., cocaine) responding. The sequential activation of hM3D(G_q) and KORD DREADDs within the same neuronal population validated the role of the VTA-AcbSh circuit in reinforced responding for concurrently available natural and drug rewards. Collectively, the VTA-AcbSh circuit is fundamentally involved in behavioral allocation affording a key target for the development of novel pharmacotherapies.

Neuroimmunity drives the pathophysiology of Parkinson's disease (PD). This disease affects both the central and peripheral nervous systems. The immune system is engaged through the progressive accumulation of alpha-synuclein (α-syn), a driver of immunity and a pathological hallmark of PD. Consequent α-syn-induced immune activation leads to neuronal damage. This leads not only to the activation of microglia within the central nervous system, but also to the recruitment and activation of peripheral immune cells that infiltrate the brain and contribute to a widespread immune response. Moreover, PD-associated genes and risk factors have been increasingly recognized as essential regulators of immune functions. This review summarizes the current understanding of adaptive immunity in PD and explores emerging immunomodulatory strategies that may inform future therapeutic development.

Objective: The Human Immunodeficiency Virus-1 (HIV) cell entry has been well characterized with the identification of CD4 as the main receptor and CXCR4 and CCR5 as co-receptors for the virus. However, how the virus uses the cell machinery for entry and infection is still a work-in-progress. Previously, we identified that the Pannexin-1 (Panx-1) channel, extracellular ATP, and purinergic receptors axis are essential for HIV entry and replication in macrophages, but the mechanisms were not fully explored.

Methods: Electrophysiology, ATP quantifications, confocal, HIV entry and replication experiments were used to determine the role of Panx-1 channels in HIV entry.

Results: Here, we identified that HIV or gp120 induces Panx-1 channel opening in association with ATP secretion, purinergic activation, and CCR5/CXCR4/actin clustering to enable HIV entry. Blocking Panx-1 channel opening, ATP secretion, or purinergic signaling prevented co-receptor clustering, HIV entry, and subsequent replication in multiple cell types.

Conclusion: We conclude that gp120 binding to the cell induces Panx-1 opening to promote the clustering of CCR5 or CXCR4 to the site of CD4-gp120 contact to aid viral entry.