Neuropharmacology最新文献

Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Transformation of pro-interleukin (IL)-1β into a mature IL-1β via active inflammasome may be related to the progression of PD. Therefore, the modification of inflammasome activity may be a potential therapeutic strategy for PD. Inosine has been shown to exert anti-inflammatory effects in various disease models. In this study, we evaluated inosine's inhibitory effects on the microglial NLRP3 inflammasome, which may be related to the dopaminergic neuroprotective effects of inosine. Inosine suppresses lipopolysaccharides (LPS)-induced NLRP3 inflammasome activation in BV-2 microglial cells dose dependently. When SH-SY5Y cells were treated with conditioned medium from BV-2 cells treated with LPS and inosine, an NLRP3 inhibitor, or a caspase-1 inhibitor, the viability of SH-SY5Y cells was reduced indicating that LPS-induced microglial inflammasome activation could contribute to neuronal death. Inosine's modulatory effect on NLRP3 inflammasome activity appears to rely on the adenosine A_2A and A₃ receptors activation, as A_2A or A₃ receptor antagonists reversed the amelioration of NLRP3 activation by inosine. In addition, inosine treatment attenuated intracellular and mitochondrial ROS production mediated by LPS and this effect might be related to attenuation of NLRP3 inflammasome activity, as the antioxidant, N-acetyl cysteine ameliorated LPS-induced activation of the inflammasome. Finally, we assessed the inosine's neuroprotective effects via inflammasome activity modulation in mice receiving an intranigral injection of LPS. Immunohistochemical analysis revealed that LPS caused a significant loss of nigral dopaminergic neurons, which was mitigated by inosine treatment. LPS increased NLRP3 expression in IBA1-positive microglial cells, which was attenuated by inosine injection. These findings indicate that inosine can rescue neurons from LPS-induced injury by ameliorating NLRP3 inflammasome activity. Therefore, inosine could be applied as an intervention for neuroinflammatory diseases such as Parkinson's disease.

Individuals with prenatal alcohol exposure (PAE) are at a higher risk for developing alcohol use disorder (AUD). Using a rat model of moderate PAE (mPAE) on gestational day 12 (G12; ∼2nd trimesters in humans), a critical period for amygdala development, we have shown disruptions in medial central amygdala (CeM) function, an important brain region associated with the development of AUD. In addition to this, acute ethanol (EtOH) increases GABA transmission in the CeM of rodents in a sex-dependent manner, a mechanism that potentially contributes to alcohol misuse. How mPAE alters acute alcohol's effects within the CeM is unknown. Given these findings, we investigated how mPAE may interact with acute alcohol to alter neuronal and synaptic mechanisms in the CeM of adolescent rats in order to understand PAE-induced alcohol-related behaviors. Under basal conditions, mPAE males showed reduced rheobase, indicative of reduced excitability, and females showed a reduction in GABA transmission, indicated by lower spontaneous inhibitory postsynaptic currents (sIPSCs). We found that acute EtOH increased sIPSCs in control males at the middle concentration (66 mM), while mPAE males showed increased sIPSCs only at the highest tested concentration (88 mM). Adolescent females, regardless of PAE status, were largely insensitive to EtOH's effects at all tested concentrations. However, mPAE females showed a significant increase in sIPSCs at the highest tested concentration (88 mM). Overall, these findings support the hypothesis that mPAE leads to sex-specific changes in synaptic activity and neuronal function. Future research is needed to better understand the specific mechanisms by which acute EtOH affects neurotransmission in the adolescent brain of individuals with a history of PAE.

Epilepsy, a prevalent neurological disorder characterized by spontaneous recurrent seizures, significantly impacts physiological and cognitive functions. Emerging evidence suggests a crucial role for metabolic factors, particularly lactate, in epilepsy. We discuss the applicability of the astrocyte-neuron lactate shuttle (ANLS) model during acute seizure events and examine lactate's metabolic adaptation in epilepsy progression. Additionally, the roles of lactate metabolism in microglia and oligodendrocytes are considered, aiming to supplement our understanding of neuro-glial metabolic interactions as extensions of the ANLS model. Additionally, lactate modulates neuronal excitability via its interaction with hydroxycarboxylic acid receptor 1 (HCAR1), alongside additional mechanisms involving acid-sensing ion channels (ASICs) and ATP-sensitive potassium (KATP) channels, which contribute as secondary modulatory pathways. In conclusion, we propose that lactate functions as more than a mere fuel source in the epileptic brain, offering potential insights into new therapeutic targets for seizure control.

Hyperoside, a natural flavonoid, exhibits a wide range of biological activities, including analgesic effects on acute and chronic inflammatory pain. This study illustrates that repeated intraperitoneal administration or microinjection of hyperoside into the ventrolateral periaqueductal grey (vlPAG) alleviated mechanical allodynia, cold allodynia, and abnormal gait induced by spared nerve injury (SNI) in male mice. Furthermore, repeated hyperoside administration suppressed SNI-induced astrocyte reactivity in the vlPAG. Moreover, hyperoside alleviated the pain behaviors resulting from the pharmacogenetic activation of vlPAG astrocytes. These results suggest that hyperoside may effectively mitigate neuropathic pain and inhibit astroglial reactivity in the vlPAG, highlighting its potential as a viable therapeutic intervention for chronic neuropathic pain.

Cannabidiol has been shown to ameliorate neuropathic pain and its affective components. Previous studies highlighted the pharmacological interaction between the CBD and opioid system, particularly the MOR, but the understanding of the interaction between CBD and kappa opioid receptor (KOR), physiologically stimulated by the endogenous opioid dynorphin, remains elusive. We assessed the pharmacological interactions between CBD and nor-BNI, a selective KOR antagonist in a rat neuropathic pain model. We show an increase in dynorphin peptide and its KOR receptors in the hippocampus' dentate gyrus (DG) of neuropathic rats showing allodynia, and memory deficits. Consistent with these findings, neuropathic pain was associated with long-term potentiation (LTP) impairment in the entorhinal cortex-DG, also referred to as the lateral perforant pathway (LPP). Moreover, a downregulation of the endocannabinoid 2-AG and an upregulation of the cannabinoid CB1 receptors in the DG were detected in neuropathic pain animals. Either an acute KOR antagonist administration or one-week CBD treatment normalized dynorphin levels and improved affective symptoms, LTP and receptor expression, whereas only CBD showed an anti-allodynic effect. In addition, CBD normalized the SNI-induced changes in neuroplasticity as well as endocannabinoid and GABA levels in the DG. Noteworthy, the acute blockade of the KOR carried out after CBD repeated administration causes the re-installment of some neuropathic condition symptoms. As a whole, these original results indicate a critical relationship between the adaptive changes in the hippocampus produced by CBD and the need to maintain the recovered physiological dynorphin tone to preserve the therapeutic effect of CBD in neuropathic rats.

Objective: Autoantibody-associated psychosis represents a distinct disease subgroup of patients with schizophrenia with a suspected autoimmune origin. Although preliminary studies have suggested adjunctive drug treatment strategies targeting the immune system, further validation of these findings is warranted. Autoantibodies against SFT2D2 have been identified in patients with schizophrenia. ApoE^-/- mice immunized with SFT2D2-peptides can be used as a model for testing immunotherapy in this subgroup of patients. We used the atypical antipsychotic drug clozapine and immunosuppressant rapamycin to test their effects in this mouse model.

Methods: The mice were evaluated for cognitive and schizophrenia-like behaviors. Following behavioral testing, brain samples were collected for analyzing specific pathological changes and dendritic spine formation.

Results: Clozapine and rapamycin reversed impaired pre-pulse inhibition, motor impairment, and improved cognitive ability in ApoE ^-/- mice exposed to anti-SFT2D2 immunoglobulin G. Immunohistochemical assays revealed that both clozapine and rapamycin significantly reduced activated microglial infiltration and restored neuronal dendritic spine density.

Conclusions: Our study results suggested that clozapine and rapamycin possess therapeutic benefits for managing autoimmune psychosis and provide mechanistic insights into immunotherapies involving immunosuppressive agents.

Neuropeptide Y (NPY) is the most abundant neuropeptide in the brain. It exerts anxiolytic and anticonvulsive actions, reduces stress and suppresses fear memory. While its effects at the behavioral and cellular levels have been well studied, much less is known about the modulation of physiological activity patterns at the network level. We therefore studied the impact of NPY on two prominent, memory-related hippocampal activity patterns, gamma oscillations and sharp wave-ripple complexes in C57BL/6 male mice. Using established in vitro brain slice models for both patterns, we assessed the effects of NPY and receptor-specific agonists and antagonists on network activity in the CA3 and CA1 subnetworks. We report that NPY strongly suppresses sharp waves, and has significant, but much weaker effects on the power of carbachol-induced gamma oscillations. Both effects are primarily mediated via Y2 receptors. Additionally, NPY effects are much more prominent in the CA1 region compared to CA3. Our results show pattern- and region-specific effects of NPY on hippocampal networks, which suggest specific modulatory actions on hippocampus-dependent memory processes.

Background: Evenamide, a glutamate modulator, is currently in phase 3 of development as add-on treatment to antipsychotics in patients with inadequate response or treatment-resistant schizophrenia. This study was designed to determine if patients with chronic schizophrenia inadequately responding to a second-generation antipsychotic would benefit from add-on treatment with evenamide at a dose of 30 mg bid.

Methods: Study 008A was a prospective, 4-week, randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and efficacy of oral doses of evenamide of 30 mg bid in patients with chronic schizophrenia treated at stable therapeutic doses of a second-generation antipsychotic. Outpatients aged ≥18 years, both males and females, with a diagnosis of schizophrenia (DSM-V), who had been receiving antipsychotics for at least 2 years at stable doses, but still symptomatic (PANSS 70-85, CGI-S 4-6, predominant positive symptoms), were eligible for the study. Patients were randomised equally to evenamide 30 mg or placebo, given bid, after completing a 21-day screening period. The primary outcome (change from baseline in PANSS total score) was assessed weekly, with the primary endpoint at 4 weeks.

Results: A total of 291 patients were enrolled, of which 11 (3·8%) discontinued prematurely, overall. Add-on treatment with evenamide was associated to a statistically significant (the absolute difference of the two treatment groups for the PANSS Total at Day 29, primary efficacy endpoint, was = 2·5 [p-value<0.05] that is associated with a Cohen's d effect size = 0·33) and clinically meaningful benefit compared to placebo across all efficacy measures, and was well tolerated.

Conclusion: The demonstration of statistically significant and clinically meaningful benefit of evenamide, a glutamate modulator, as add-on treatment in patients with chronic schizophrenia inadequately responding to their second-generation antipsychotic may represent a new treatment paradigm for this population.