Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.

Parkinson's disease (PD) is the main neurodegenerative disorder affecting motor activity, there are different pathophysiological pathways contributing to its development including oxidative stress, neuroinflammation, Lewy's bodies accumulation, and impaired autophagy. Vinpocetine is an herbal extract with antioxidant and anti-inflammatory activities that may counteract pathophysiologic neurodegeneration pathways. Moreover, Lactobacillus is a probiotic that can modulate the gut-brain axis and provide the body with the needed precursors of antioxidants and anti-inflammatory mediators. In the current study PD was induced experimentally in Sprague Dawley rats with rotenone (2.5 mg/kg, i.p, daily) for 60 days, vinpocetine; Vinpo (20 mg/kg, orally, daily) and Lactobacillus; Lacto (2.7 × 10⁸ CFU/ml, orally, daily) were applied as protective treatment. Vinpocetine and Lactobacillus treatment significantly ameliorated motor function by increasing distance traveled and rearing frequency in the open field test with a concomitant increase in falling time from both the accelerating rotarod and the wire screen test. Moreover, vinpocetine and Lactobacillus treatment upregulates tyrosine hydroxylase expression (the rate-limiting enzyme in dopamine synthesis), leading to enhanced dopamine synthesis and improved dopaminergic function with regression of histopathological hallmarks. Antioxidant GSH levels were significantly increased after vinpocetine and Lactobacillus treatment with a significant decrease in MDA content in brain homogenates. Furthermore, vinpocetine and Lactobacillus treatment significantly decreased striatal inflammatory markers; nitrite, IL-1β and TNF-α. Proteinopathies were regressed with a substantial decrease in striatal α-synuclein and tau content. In conclusion, vinpocetine and Lactobacillus treatment reduced rotenone neurotoxicity with improved dopamine release and motor activity with correction of oxidative burden, neuro-inflammation, and proteinopathy.

Excessive alcohol use damages the brain, especially corticolimbic regions such as the hippocampus and rhinal cortices, leading to learning and memory problems. While neuroimmune reactivity is hypothesized to underly alcohol-induced damage, direct evidence of the causal role of microglia, brain-resident immune cells, in this process is lacking. Here, we depleted microglia using PLX5622 (PLX), a CSF1R inhibitor commonly used in mice, but rarely in rats, and assessed cell death following binge-like alcohol exposure in male rats. Eleven days of PLX treatment depleted microglia > 90%. Further, PLX treatment prevented alcohol-induced neuronal death in the hippocampus and rhinal cortices, as the number of FluoroJade-B-positive cells (dying neurons) was reduced to control diet levels. This study provides direct evidence that alcohol-induced microglial reactivity is neurotoxic in male rats. Improved understanding of alcohol-microglia interactions is essential for developing therapeutics that suppress pro-cytotoxic and/or amplify protective microglia activity to relieve alcohol-related damage.

The NLRP3 inflammasome signaling cascade activation is a significant contributor to the initiation and progression of Parkinson's disease (PD). Recent evidence supports that targeting NLRP3 inflammasome assembly could be a potential strategy to halt PD progression. The molecular mechanism of the olfactory-brain axis in mediating PD remains elusive. The current study explores that MPTP exposure to C57BL/6 mice leads to glial cell activation and impairs the olfactory function. The role of NLRP3 inflammasome activation in the olfactory bulb and the brain mediating neuroinflammation and neurodegeneration by activating multiple inflammatory pathways is explored. Loganic acid (LA), an iridoid glycoside, has been shown to provide antioxidant, anti-inflammatory, and inhibit microglial activation. Our results in-vitro studies demonstrated that LA treatment in MPP⁺-induced microglial cells inhibits NLRP3 inflammasome assembly, halts phagocytosis, and downregulates the release of pro-inflammatory cytokines such as IL-1β and IL-18. Further, results confirm that LA increases the neuronal differentiation markers and assists neurite growth. To correlate the in-vitro experiments with the in-vivo study, LA treatment prevented the loss of olfactory and motor function. In immunoblotting, LA treatment significantly inhibits the expression of NLRP3 inflammasome signaling cascade when compared to the MPTP group of the olfactory bulb and substantia nigra. Computational studies on LA on IL-β, NLRP3, caspase-1, and ASC also support strong evidence in the downregulation of inflammasome and cytokines through potential non-covalent interactions. The results confirm the neuroprotective effect of LA in PD by halting the NLRP3 inflammasome activation in the olfactory bulb and nigra region of the mice.

Spinal microglial activation and the polarization towards the M1 phenotype are implicated in the pathological process of neuropathic pain. Extensive research has elucidated that growth and differentiation factor 11 (GDF11), a constituent of the transforming growth factor-β (TGF-β) superfamily, exerts inhibitory effects on macrophage activation and mitigates inflammatory responses via the activation of TGF-β receptor type I (TGF-βR1). Nonetheless, the influence of GDF11 on spinal microglial polarization and its role in neuropathic pain remains to be ascertained. In the present investigation, a neuropathic pain model was induced via a spared nerve injury (SNI) procedure on the sciatic nerve in male mice. The impact of GDF11 on microglial polarization and neuropathic pain in SNI-subjected mice was evaluated through pain behavior assessments, WB, IF, qRT-PCR, and ELISA. Our findings revealed a significant downregulation of spinal GDF11 and TGF-βR1 expression levels in microglia of mice subjected to SNI. Furthermore, GDF11 treatment notably reversed the mechanical allodynia and thermal hyperalgesia, inhibited M1 microglial polarization, and attenuated neuroinflammatory processes by modulating the SMAD2/NF-κB in SNI mice. However, the analgesic effects of GDF11 on pain hypersensitivity and its modulatory influence on spinal microglial polarization were abrogated by the application of a specific antagonist of TGF-βR1, or the TGF-βR1 siRNA. In summary, GDF11 effectively ameliorated mechanical allodynia and thermal hyperalgesia, suppressed M1 microglial polarization, and alleviated neuroinflammation via the regulation of the TGF-βR1/SMAD2/NF-κB pathway in mice with SNI. These findings suggest that GDF11 holds promise as a therapeutic modality for the management of neuropathic pain.

Alzheimer's disease (AD) is the most common form of dementia. Characterized by progressive neurodegeneration, AD typically begins with mild cognitive decline escalating to severe impairment in communication and responsiveness. It primarily affects cerebral regions responsible for cognition, memory, and language processing, significantly impeding the functional independence of patients. With nearly 50 million dementia cases worldwide, a number expected to triple by 2050, the need for effective treatments is more urgent than ever. Recent insights into the association between obesity, type 2 diabetes mellitus, and neurodegenerative disorders have led to the development of promising treatments involving antidiabetic and anti-obesity agents. One such novel promising candidate for addressing AD pathology is a lipidized analogue of anorexigenic peptide called prolactin-releasing peptide (palm¹¹-PrRP31). Interestingly, anorexigenic and orexigenic peptides have opposite effects on food intake regulation, however, both types exhibit neuroprotective properties. Recent studies have also identified ghrelin, an orexigenic peptide, as a potential neuroprotective agent. Hence, we employed both anorexigenic and orexigenic compounds to investigate the common mechanisms underpinning their neuroprotective effects in a triple transgenic mouse model of AD (3xTg-AD mouse model) combining amyloid-beta (Aβ) pathology and Tau pathology, two hallmarks of AD. We treated 3xTg-AD mice for 4 months with two stable lipidized anorexigenic peptide analogues - palm¹¹-PrRP31, and liraglutide, a glucagon-like peptide 1 (GLP-1) analogue - as well as Dpr³-ghrelin, a stable analogue of the orexigenic peptide ghrelin, and using the method of immunohistochemistry and western blot demonstrate the effects of these compounds on the development of AD-like pathology in the brain. Palm¹¹-PrRP31, Dpr³-ghrelin, and liraglutide reduced intraneuronal deposits of Aβ plaque load in the hippocampi and amygdalae of 3xTg-AD mice. Palm¹¹-PrRP31 and Dpr³-ghrelin reduced microgliosis in the hippocampi, amygdalae, and cortices of 3xTg-AD mice. Palm¹¹-PrRP31 and liraglutide reduced astrocytosis in the amygdalae of 3xTg-AD mice. We propose that these peptides are involved in reducing inflammation, a common mechanism underlying their therapeutic effects. This is the first study to demonstrate improvements in AD pathology following the administration of both orexigenic and anorexigenic compounds, highlighting the therapeutic potential of food intake-regulating peptides in neurodegenerative disorders.

Regulatory T (Treg) cells contribute to white matter repair following ischemic stroke, but their limited availability in circulation restricts their therapeutic potential. Exercise, as a non-invasive and effective rehabilitation method, has been shown to restore Treg balance in diseases. This study explores the effects of treadmill training on Treg upregulation and its influence on myelin repair and functional recovery in rats with middle cerebral artery occlusion (MCAO). After four weeks of treadmill training, we analyzed the proportion of Treg cells (Tregs), FOXP3 expression, and oligodendrocyte-related protein levels using flow cytometry, immunofluorescence, and Western blotting. Myelin structure was examined with transmission electron microscopy (TEM), while motor coordination and balance were assessed using the fatigue rotarod and CatWalk analysis systems. To further explore the role of Tregs, the FOXP3 inhibitor P60 was used to inhibit Treg activity. The findings of our study indicate that training on a treadmill supports the maturation of oligodendrocytes, leads to an increase in myelin-associated proteins and the thickness of myelin, and promotes the recovery of motor function. Inhibition of Treg activity diminished these benefits, highlighting Tregs' key role in exercise-induced remyelination. These findings suggest that treadmill training facilitates myelin regeneration and functional recovery by upregulating Tregs, offering potential new strategies for stroke treatment.

Human immunodeficiency virus (HIV) infection produces neurological comorbidities including HIV-associated neurocognitive disorder (HAND) and chronic pain. HIV also increases the risk of developing an alcohol use disorder (AUD). With the rising prevalence of AUD in women and people with HIV (PWH), understanding the neurobiological impact of alcohol in these populations is important. We examined proteomic alterations in the hippocampus and anterior cingulate cortex (ACC), brain regions critical for cognition and affective pain, in a female rhesus macaque model of chronic binge alcohol administration and SIV infection. Adult female rhesus macaques received either chronic binge alcohol (CBA, 13-14 g/kg/week of alcohol) or water (VEH) via gastric catheter. All animals were inoculated with simian immunodeficiency virus (SIV_mac251) and treated with antiretroviral therapy (ART). Brain samples were processed for proteomic analysis, and quantitative discovery-based proteomics identified differentially expressed proteins in both brain regions comparing CBA treatment to VEH. Ingenuity Pathway Analysis (IPA) was also used to predict pathway activation. CBA significantly altered 147 proteins in the hippocampus and 176 proteins in the ACC. IPA revealed alterations in 39 canonical pathways in the hippocampus and 62 canonical pathways in the ACC. Fourteen common canonical pathways were enriched in both regions, including synaptogenesis and protein kinase A (PKA) signaling. These discoveries expand our understanding of how alcohol alters proteins of critical signaling pathways in vulnerable brain regions in the context of SIV/HIV infection and may lead to the development of new pharmacological treatment avenues for neurological dysfunction in women with HIV who use alcohol.

Alzheimer's disease (AD) is the most common cause of dementia worldwide, characterized by accumulation of amyloid-β protein and hyperphosphorylated tau protein in the brain. Neuroinflammation, resulting from chronic activation of brain-resident innate immune cells as well as enhanced peripheral leukocyte access across the blood-brain barrier, crucially affects AD progression. In this context, TNFSF10, a cytokine substantially expressed in the AD brain, has been shown to modulate both the innate and the adaptive branches of the immune response in AD-related neuroinflammation. In this study, we explored whether a TNFSF10-neutralizing treatment could represent a tool to re-balance the overall overshooting inflammatory response in a mouse model of AD. Specifically, 3xTg-AD mice were treated sub-chronically with an anti-TNFSF10 monoclonal antibody for three months, and were then sacrificed at 15 months. TNFSF10 neutralization reduced the expression of the inflammatory marker CD86, inversely related to levels of the anti-inflammatory marker CD206 in the brain of 3xTg-AD mice, suggesting a switch of microglia towards a neuroprotective phenotype. Similar results were observed in the splenic macrophage population. Moreover, flow cytometry revealed a significant decrease of CD4⁺CD25⁺FOXP3⁺ T regulatory cells as well as reduced number of CD11b⁺LY6C^high proinflammatory monocytes in both the brain and the spleen of 3xTg-AD mice treated with anti-TNFSF10 monoclonal antibody. Finally, the treatment resulted in lower count of splenic CD4⁺ and CD8⁺ T cells expressing PD1. The data suggest that TNFSF10 system-targeted treatment effectively restrain overshooting central and peripheral inflammation by rebalancing the overall immune response, mitigating the progression of AD pathology.

PKR, a kinase implicated in inflammation, accumulates in the brain, but its role in neuroinflammation-related depression is poorly understood. This study aimed to investigate whether pharmacological PKR inhibition using C16 (PKR inhibitor) could reverse LPS-induced neuroinflammation and depressive-like behaviors. Mice (C57BL/6J, 20-22 g, 6-8 weeks old) were administered LPS intraperitoneally for three days to induce depressive-like behavior and neuroinflammation. Simultaneously, mice were treated with C16 (a pharmacological PKR inhibitor) intraperitoneally for the same duration, followed by behavioral assessments. After euthanasia, brain-hippocampus tissues were collected for biochemical analysis. To validate these in vivo findings, BV2 and HT22 cells were cultured and subjected to pharmacological and biochemical analysis. LPS treatment significantly increased hippocampal neuroinflammation (GFAP/IBA-1 p < 0.001), cytokine production (IL-1β, IL-6, TNF-α, p < 0.05), PKR phosphorylation (p < 0.05), and inflammatory signaling (NLRP3/ASC, p < 0.001). Concomitantly, LPS exposure induced depressive-like symptoms (p < 0.001), impaired synaptic function (Synasin-1/SNAP25, p < 0.05), spine numbers (p < 0.001), and downregulated brain-derived neurotrophic factor (BDNF) /TrkB signaling (p < 0.001). Importantly, these effects were attenuated by C16, a PKR inhibitor. C16 also reduced LPS-induced ER stress markers in the hippocampus (p < 0.05). Interestingly, K252a, a BDNF/TrkB inhibitor, reversed the protective effects of C16, increasing both neuroinflammation (p < 0.001) and depressive symptoms (p < 0.001) in LPS-treated mice. Notably, in vitro studies using BV2 and HT22 cells corroborated these findings. In conclusion, these findings suggest that PKR is critical in mediating LPS-induced neuroinflammation and depressive-like behaviors, potentially through interactions with BDNF/TrkB signaling.