NeuroImmune pharmacology and therapeutics最新文献

Objectives: Opioids including morphine and DAMGO activate mu-opioid receptors (MOR), increase intracellular reactive oxygen species (ROS) levels, and induce cell death. Ferrous iron (Fe²⁺) through Fenton-like chemistry increases ROS levels and endolysosomes are "master regulators of iron metabolism" and contain readily-releasable Fe²⁺ stores. However, mechanisms underlying opioid-induced changes in endolysosome iron homeostasis and downstream-signaling events remain unclear.

Methods: We used SH-SY5Y neuroblastoma cells, flow cytometry, and confocal microscopy to measure Fe²⁺ and ROS levels and cell death.

Results: Morphine and DAMGO de-acidified endolysosomes, decreased endolysosome Fe²⁺ levels, increased cytosol and mitochondria Fe²⁺ and ROS levels, depolarized mitochondrial membrane potential, and induced cell death; effects blocked by the nonselective MOR antagonist naloxone and the selective MOR antagonist β-funaltrexamine (β-FNA). Deferoxamine, an endolysosome-iron chelator, inhibited opioid agonist-induced increases in cytosolic and mitochondrial Fe²⁺ and ROS. Opioid-induced efflux of endolysosome Fe²⁺ and subsequent Fe²⁺ accumulation in mitochondria were blocked by the endolysosome-resident two-pore channel inhibitor NED-19 and the mitochondrial permeability transition pore inhibitor TRO.

Conclusions: Opioid agonist-induced increases in cytosolic and mitochondrial Fe²⁺ and ROS as well as cell death appear downstream of endolysosome de-acidification and Fe²⁺ efflux from the endolysosome iron pool that is sufficient to affect other organelles.

Objectives: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory autoimmune disease characterized by high levels of infected immortalized T cells in circulation, which makes it difficult for antiretroviral (ART) drugs to work effectively. In previous studies, we established that Apigenin, a flavonoid, can exert immunomodulatory effects to reduce neuroinflammation. Flavonoids are natural ligands for the aryl hydrocarbon receptor (AhR), which is a ligand activated endogenous receptor involved in the xenobiotic response. Consequently, we tested Apigenin's synergy in combination with ART against the survival of HTLV-1-infected cells.

Methods: First, we established a direct protein-protein interaction between Apigenin and AhR. We then demonstrated that Apigenin and its derivative VY-3-68 enter activated T cells, drive nuclear shuttling of AhR, and modulate its signaling both at RNA and protein level.

Results: In HTLV-1 producing cells with high AhR expression, Apigenin cooperates with ARTs such as Lopinavir (LPN) and Zidovudine (AZT), to impart cytotoxicity by exhibiting a major shift in IC₅₀ that was reversed upon AhR knockdown. Mechanistically, Apigenin treatment led to an overall downregulation of NF-κB and several other pro-cancer genes involved in survival.

Conclusions: This study suggest the potential combinatorial use of Apigenin with current first-line antiretrovirals for the benefit of patients affected by HTLV-1 associated pathologies.

Objectives: Zika virus (ZIKV) has become an epidemic in several countries and was declared a major public health issue by the WHO. Although ZIKV infection is asymptomatic or shows mild fever-related symptoms in most people, the virus can be transmitted from a pregnant mother to the fetus, resulting in severe brain developmental abnormalities, including microcephaly. Multiple groups have identified developmental neuronal and neuronal progenitor compromise during ZIKV infection within the fetal brain, but little is known about whether ZIKV could infect human astrocytes and its effect on the developing brain. Thus, our objective was to determine astrocyte ZiKV infection in a developmental-dependent manner.

Methods: We analyze infection of pure cultures of astrocytes and mixed cultures of neurons and astrocytes in response to ZIKV using plaque assays, confocal, and electron microscopy to identify infectivity, ZIKV accumulation and intracellular distribution as well as apoptosis and interorganelle dysfunction.

Results: Here, we demonstrated that ZIKV enters, infects, replicates, and accumulates in large quantities in human fetal astrocytes in a developmental-dependent manner. Astrocyte infection and intracellular viral accumulation resulted in neuronal apoptosis, and we propose astrocytes are a ZIKV reservoir during brain development.

Conclusions: Our data identify astrocytes in different stages of development as major contributors to the devastating effects of ZIKV in the developing brain.

Tunneling nanotubes (TNTs), also called cytonemes or tumor microtubes, correspond to cellular processes that enable long-range communication. TNTs are plasma membrane extensions that form tubular processes that connect the cytoplasm of two or more cells. TNTs are mostly expressed during the early stages of development and poorly expressed in adulthood. However, in disease conditions such as stroke, cancer, and viral infections such as HIV, TNTs proliferate, but their role is poorly understood. TNTs function has been associated with signaling coordination, organelle sharing, and the transfer of infectious agents such as HIV. Here, we describe the critical role and function of TNTs during HIV infection and reactivation, as well as the use of TNTs for cure strategies.

Objectives: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC.

Methods: 29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels.

Results: PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region.

Conclusions: The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.

Background: Pharmacological approaches that boost neuroprotective regulatory T cell (Treg) number and function lead to neuroprotective activities in neurodegenerative disorders.

Objectives: We investigated whether low-dose interleukin 2 (IL-2) expands Treg populations and protects nigrostriatal dopaminergic neurons in a model of Parkinson's disease (PD).

Methods: IL-2 at 2.5 × 10⁴ IU/dose/mouse was administered for 5 days. Lymphocytes were isolated and phenotype determined by flow cytometric analyses. To 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice, 0.5 × 10⁶ of enriched IL-2-induced Tregs were adoptively transferred to assess the effects on nigrostriatal neuron survival.

Results: IL-2 increased frequencies of CD4⁺CD25⁺CD127^lowFoxP3⁺ Tregs that express ICOS and CD39 in blood and spleen. Adoptive transfer of IL-2-induced Tregs to MPTP-treated recipients increased tyrosine hydroxylase (TH)⁺ nigral dopaminergic neuronal bodies by 51% and TH⁺ striatal termini by 52% compared to control MPTP-treated animal controls.

Conclusions: IL-2 expands numbers of neuroprotective Tregs providing a vehicle for neuroprotection of nigrostriatal dopaminergic neurons in a pre-clinical PD model.