Neuropharmacology最新文献

Spinal cord injury (SCI) triggers persistent neuroinflammation, primarily driven by aberrant astrocyte activation, which exacerbates secondary neurodegeneration. Indole-3-propionic acid (IPA), a tryptophan-derived metabolite produced by the gut microbiota, has recently emerged as a potent anti-inflammatory agent in neurological disorders. However, its therapeutic potential and underlying mechanisms in SCI remain unexplored. In this research, using a TNF-α-stimulated astrocyte model in vitro and a mouse SCI model in vivo, we demonstrated that IPA significantly attenuated the expression of pro-inflammatory mediators (IL-6, IL-1β, iNOS, COX-2, CCL2, CXCL2, CXCL10) in astrocytes, both in vitro and in vivo. Transcriptomic and mechanistic investigations reveal that IPA suppressed NF-κB/MAPK signaling pathways by activating the aryl hydrocarbon receptor (AhR). In SCI mice, IPA treatment reduced glial scar formation, enhanced neuronal survival, and improved long-term motor function, as evidenced by increased BMS scores, inclined plane test performance, and gait coordination. MRI and histopathological analyses further confirmed reduced lesion volume and preserved tissue integrity. Our findings demonstrate that gut microbiota-derived IPA acts through the AhR/NF-κB/MAPK axis to mitigate secondary spinal cord injury by exerting anti-inflammatory and neuroprotective effects. This work not only provides novel pharmacological insights into a metabolite-based approach for SCI treatment but also establishes IPA as a promising endogenous metabolite therapy with high translational potential.

The ventral tegmental area (VTA), nucleus accumbens (NAc) and insular cortex (IC) are brain regions implicated in addiction. However, the involvement of heroin-induced neuroadaptations in these regions is not fully uncovered. Here, we used male and female Long Evans rats to investigate the causal roles of two parallel pathways: VTA→IC and VTA→NAc in opioid-driven behaviors, related neuroadaptations and neural mechanisms by which environmental enrichment (EE) attenuates drug taking and seeking. Our findings are: 1) confirmation that the VTA→IC and VTA→NAc pathways consist of dopamine (DA) and nonDA neurons; 2) demonstration that both pathways are involved in heroin intravenous self-administration (IVSA), reinstatement of heroin seeking and conditioned place preference; 3) dopamine D3 receptor (D3R) mRNA is expressed in the IC, predominantly on glutamate and GABA neurons; 4) dopamine D1 receptors (D1Rs), co-localized with D3Rs, are downregulated in IC and upregulated in NAc following heroin IVSA; 5) Heroin IVSA had no significant effect on D3R and mu opioid receptor (MOR) mRNA expression in these regions; 6) EE reversed heroin-induced neuroadaptations in NAc, but not in IC; 7) heroin-seeking reinstating cues activated cFos in VTA DA and nonDA cells and 8) EE attenuated cue-induced cFos in a manner correlated with the cues' ability to reinstate drug seeking. These results indicate that heroin IVSA causes region-specific, bi-directional neuroadaptations of D1Rs and that EE reverses these neuroadaptations in the NAc. This reversal effect, along with the blunting of drug-cue-induced VTA cFos activation in DA and nonDA cells, might constitute mechanisms by which EE reduces relapse.

Bipolar disorders (BD) are defined by a chronic recurrence of manic and depressive phases. Along with mood, acute phases are associated with altered emotions. The biological underpinnings of these changes are unresolved, mostly because modeling the cycling nature of BD is still a major challenge in preclinical studies. One pharmacological model is based on GBR 12909 administration, a dopamine transporter inhibitor aiming at mimicking some dimensions of mania. Recent findings indicate that this model generates a mixed phenotype, combining hyperlocomotion with negative hedonic biases and anxiety. These studies have only been performed in male animals, and other behavioral dimensions relevant for BD remain to be explored, in particular recognition of conspecific emotional states and reactivity to danger. The objective of this study is to further characterize the GBR model in mice of both sexes by introducing two novel behavioral assays, the sweeping/looming disk and the negative emotion recognition tasks to evaluate response to threat and emotion discrimination. First, we replicated the previous results in the GBR model: higher anxiety, hyperlocomotion, anhedonia in males. These phenotypes were less pronounced and did not reach significance in females. GBR also induced a hypersensitivity to threat in both sexes in the sweeping/looming disk. GBR abolished preference for the emotional target only in males, suggesting altered emotion recognition. This work introduces new phenotypic dimensions relevant to study BD and highlights the necessity to study both sexes which are not strictly equivalent in their behavioral responses.

Ischemic stroke (IS) represents a significant global health burden with increasing incidence, creating an urgent need for novel therapeutic approaches. This study explored the neuroprotective effects of nicotinamide adenine dinucleotide phosphate (NADPH) in preserving blood-brain barrier (BBB) integrity and promoting angiogenesis after IS. Through network pharmacology analysis and molecular docking, five key molecular targets of NADPH in IS were identified: HIF-1α, SRC, NLRP3, CASP3, and AKT1. In vivo, NADPH treatment conferred significant protection against cerebral ischemia in the transient middle cerebral artery occlusion (tMCAO) model. At the optimal dose of 7.5 mg/kg, it substantially reduced infarct volume (∼50%), attenuated cerebral edema (from 81% to 76%), improved neurological function (∼58%), and preserved BBB integrity. Mechanistically, NADPH protected the BBB by upregulating key tight junction (TJ) proteins, including a ∼29% increase in ZO-1 expression, with electron microscopy confirming strengthened TJ structure. NADPH also reduced the protein levels of matrix metalloproteinase-9 (MMP9) and caveolin-1 by ∼23% and 50%, respectively. Furthermore, it suppressed NLRP3 inflammasome activation, decreased the expression of NLRP3 (∼14%), ASC (∼24%), Caspase-1 (∼30%), and interleukin-1β (IL-1β; ∼16%), thereby attenuating inflammation. In vitro, NADPH enhanced endothelial cell proliferation, migration, and tube formation under oxygen-glucose deprivation (OGD) conditions. Additionally, NADPH further elevated the expression of key pro-angiogenic markers, increasing HIF-1α protein by ∼77.1% and vascular endothelial growth factor (VEGF) by ∼44.8% at day 7 post-tMCAO. These findings suggest that NADPH confers neuroprotection in IS by preserving BBB integrity, inhibiting NLRP3 inflammasome-mediated damage, and stimulating angiogenesis through HIF-1α/VEGF signaling. Our results highlight NADPH's dual therapeutic mechanisms and its potential as a promising neuroprotective agent for IS.

Current medications for Alzheimer's disease (AD) provide symptomatic relief only and fail to prevent neurodegeneration, necessitating the development of new therapeutic agents. This study aimed to evaluate benzimidazole (BIM) analogs as potential inhibitors for AD. In vitro screening identified 1-benzyl-3-(2-((3-chlorophenyl)amino)-2-oxoethyl)-1H-benzo[d]imidazole-3-ium chloride (IMS48) as a potent inhibitor of both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with IC₅₀ values of 0.31 ± 0.04 μM and 1.85 ± 0.05 μM, respectively, outperforming the standard drug donepezil. In the in vivo study, rats were administered D-gal (300 mg/kg) and AlCl₃ (150 mg/kg) orally for three weeks to induce AD-like symptoms. Concurrently, IMS48 was administered at doses of 0.75 mg/kg and 1.5 mg/kg for 21 days. Donepezil (DON) was used as a positive control to evaluate the therapeutic efficacy of the IMS8 compound. IMS48 treatment significantly reversed behavioral alterations and improved learning ability. Histopathological analysis demonstrated that IMS48 effectively inhibited neuronal death and neurofibrillary tangles in the brain tissue. Furthermore, IMS48 restored the altered antioxidant enzyme levels (p < 0.001), reducing malondialdehyde (MDA) concentration and enhancing superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) concentrations. IMS48 also downregulated the gene expression of AChE (1.56 ± 0.10-fold and 1.71 ± 1.76-fold), APP (1.96 ± 0.17-fold and 3.39 ± 0.139-fold), BACE1 (1.92 ± 0.10-fold and 2.59 ± 0.04-fold), TNFα (2.16 ± 0.21-fold and 3.35 ± 0.17-fold), IL-1α (1.86 ± 0.236-fold and 2.56 ± 0.15-fold), and IL-1β (1.58 ± 1.82-fold and 2.32 ± 0.13-fold), associated with AD pathology and neuroinflammation. Overall, these findings highlight the neuroprotective potential of IMS48 in enhancing cognitive function and mitigating neurodegeneration in AD.

Histamine is a key regulator of wake and arousal, however its role in pharmacological modulation of wake is largely unknown. Specifically, whether histamine is always activated during pharmacologically induced wake promotion or even necessary for wake remains unclear. This study therefore measured EEG/EMG and accelerometer activity to determine sleep/wake states and locomotor activity and determined extracellular hypothalamic histamine levels using microdialysis following treatment with five wake- and sleep-modulatory compounds. We investigated the effects of three presumed wake-promoting compounds TAK-925 (danavorexton), modafinil and pitolisant as well as two presumed sleep-inducing compounds MK-8133 and Lu AF11167 in adult male mice. TAK-925 and modafinil dose-dependently prolonged wakefulness, whereas pitolisant had no effect. In contrast, TAK-925 and pitolisant increased extracellular histamine levels in hypothalamus, whereas modafinil had no effect. MK-8133 and Lu AF11167 both reduced wakefulness and decreased extracellular hypothalamic histamine levels. In vehicle-treated male mice, histamine levels were correlated with wakefulness but in pharmacologically treated male mice, this correlation was decoupled. These data demonstrate that wake can be modulated without modulating histamine signaling and vice versa.