Neuropharmacology最新文献

Mammalian brain may contain an endogenous pool of the psychedelic substance N,N-dimethyltryptamine (DMT), which may act as a co-transmitter with serotonin (5-HT). We tested the joint hypotheses that endogenous DMT would accumulate in rat brain after inhibiting monoamine oxidase with pargyline, whereas its acidic metabolite 3-indoleacetic acid (3-IAA) would accumulate after pretreatment with the inhibitor of acidic metabolic transport, probenecid. We also tested the hypothesis that pretreatment with inhibitors of plasma membrane 5-HT uptake (escitalopram, ESC) or the vesicular monoamine transporter 2 (dihydrotetrabenazine, DTBZ) would reduce the retention in brain of exogenous DMT after administration of DMT + harmine (1 mg/kg each). We first established the time courses of brain DMT, 3-IAA, and harmine concentrations for 210 min following DMT + harmine administration. The peak DMT concentration occurred at 45 min and peak 3-IAA levels at 60 min after DMT + harmine administration, with nearly complete washout of exogenous DMT at 210 min. Endogenous DMT levels were below the detection limit of our analytic method, despite pargyline pretreatment, and endogenous 3-IAA was slightly elevated by probenecid treatment, suggesting formation from tryptamine, especially in striatum. ESC did not alter the disposition of exogenous DMT or its metabolite 3-IAA, whereas DTBZ slightly increased 3-IAA formation in some brain regions. In summary, we could not detect an endogenous DMT pool in rat brain, and saw scant evidence of retention of exogenous DMT in 5-HT terminals.

The P2X7 receptor (P2X7R) is an ATP-gated ion channel belonging to the purinergic ligand-gated P2X receptor family. In the central nervous system (CNS), activation of this receptor has been proposed to play a key role in the pathogenesis of various neurodegenerative disorders. Its expression has been clearly demonstrated in microglia, where it regulates numerous cellular processes, including cell activation, cytokine release, and calcium signaling. Recent data show convincing arguments for the presence of P2X7R also in other cell types of the nervous system, such as astrocytes, oligodendrocytes, oligodendrocyte progenitor cells (OPCs) and neural progenitor cells (NPCs), although there is still some debate. The most controversial, however, is the presence and role of P2X7R in neurons. In this review, we aim to critically address this question by examining the current literature in the context of the available tools. We revisit the pharmacological regimen required to confirm the functional expression of the receptor and the mouse models that have aided in the investigation of neuronal P2X7R. Finally, we discuss some of the hypothesized contributions of neuronal P2X7R in CNS disorders.

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.