Neuropharmacology最新文献

Temozolomide (TMZ) is the primary chemotherapeutic agent for glioblastoma multiforme (GBM), but its effectiveness is limited by resistance, recurrence, and toxicity. Combining natural compounds with TMZ is a promising approach to overcome these challenges. Bacoside-A, a brain tonic derived from Bacopa monnieri with proven anticancer properties, was evaluated for its chemotherapeutic potential in U87MG cells. Our study demonstrates that the combination of Bacoside-A and TMZ significantly enhanced intracellular TMZ accumulation and promoted ROS-mediated apoptosis through Ca²⁺ influx, mitochondrial membrane depolarization, and subsequent cell death by Apoptosis. Additionally, inhibition of EGFR-driven MAPK signalling and suppression of NF-κB nuclear translocation were observed, highlighting modulation of key survival pathways. These findings suggest that Bacoside-A potentiates TMZ efficacy while enabling dose reduction, thereby minimizing toxicity. Overall, this combinatorial approach provides mechanistic insights and a potential therapeutic strategy for improving GBM treatment outcomes.

Treating patients affected by schizophrenia (SZ) remains highly challenging for drug developers. While available antipsychotics mostly reduce positive symptoms, their effects on cognitive and social deficits as well as their underlying pathophysiology remain insufficient. Disinhibition in SZ patients' cortex is considered a key player in the genesis of these symptoms and would result from N-methyl-D-aspartate receptor (NMDAr) hypofunction on interneurons. Besides, electroencephalography-based biomarkers of these mechanisms including spontaneous and evoked gamma oscillations have been highlighted. These strongly depend on NMDAr function, associate with symptoms and therefore represent translational tools for drug development. However, reversing these circuit abnormalities is challenging for the field and finding drugs engaging them would constitute a major milestone. Here, we tested three different drugs whose features attract scientists for restoration of excitation/inhibition balance: cariprazine (D2/D3 receptor partial agonist and 5-HT_2A receptor antagonist), LY379268 (mGlur2/3 receptor agonist) and donepezil (acetylcholinesterase inhibitor). We investigated their effects on spontaneous oscillations and auditory steady-state responses (ASSR, measuring evoked gamma oscillations) in a rat model of SZ induced by MK-801, a selective NMDAr blocker. MK-801 increased locomotor activity, impaired spontaneous and evoked gamma oscillations and altered spontaneous oscillations in delta, alpha and beta frequencies of male Sprague Dawley rats. Remarkably, both cariprazine and LY379268 normalized spontaneous gamma oscillations. Moreover, cariprazine normalized alpha and beta waves and LY37926 selectively corrected delta activity. Interestingly, only cariprazine mitigated the ASSR deficit. These differential normalization profiles, including cariprazine's unique broad-spectrum signature, reveal distinct patterns of circuit engagement and provide a translational pharmaco-EEG framework for circuit-level target engagement in SZ drug development.

Opioids mediate the majority of drug overdose-related deaths in the United States. Opioid-induces addictive behaviors in part via manipulation of excitatory synaptic plasticity of ventral tegmental area (VTA) dopamine cells by targeting presynaptic mu opioid receptors (MORs). Recent data demonstrate VTA GABAergic cells also exhibit excitatory long-term depression (LTD) plasticity that is cannabis susceptible. Here we identify expression of presynaptic MORs at excitatory inputs to VTA GABA cells of male/female adolescent and adult mice using electrophysiology, motivating further examination of morphine impact on synaptic plasticity of these understudied cells. Long-term (7-10 days) intraperitoneal injection of morphine eliminated both LTD and MOR agonist-induced synaptic depression in adolescent mice. Surprisingly, in adult mice chronic morphine eliminated LTD in only ∼50% of VTA GABA cells. Seven-day withdrawal following morphine treatment reversed LTD elimination in all adolescents GABA cells, but not in adults. Next, as LTD is cannabinoid receptor 1 (CB1)-dependent and endogenous opioid and cannabinoid systems have signaling overlap, we examined MOR influence on LTD. While MOR antagonist naloxone did not block LTD, pre-exposure of MOR agonist DAMGO occluded LTD, suggesting CB1 and MOR crosstalk. Collectively, this demonstrates morphine alteration of VTA GABA cell function and plasticity that potentially correlates to dependence and withdrawal, as well as age-dependent morphine impact. Further examination of opioid dependence mediated by the inhibitory reward circuit that considers age-dependence will be essential when considering targets for therapeutic interventions aimed at mitigating opioid addiction.

Remifentanil-induced postoperative hyperalgesia (RIH) delays recovery, prolongs hospitalization, and may contribute to chronic pain. The ventrolateral periaqueductal gray (vlPAG) is a critical area for processing pain and supporting opioid-based pain relief. Inside this region, glutamate (Glu) neurons and γ-aminobutyric acid (GABA) neurons work against each other to control pain signals. However, their specific roles and underlying mechanisms in RIH remain unclear. In this study, a RIH model was established by using incisional pain mice combined with continuous infusion of remifentanil. The results indicated that RIH mice showed a significant decrease in mechanical pain thresholds in both hind paws, and this hypersensitivity only occurred under the condition of remifentanil infusion combined with surgical trauma. The expression of immediate early protein (c-Fos) in the vlPAG was significantly upregulated; calcium signal recording showed that both vlPAG-Glu and vlPAG-GABA neurons were involved in the regulation of RIH. Chemical genetic activation of vlPAG-Glu or inhibition of vlPAG-GABA could alleviate hypersensitivity. Patch clamp results showed that vlPAG-Glu in RIH mice exhibited synchronous enhancement of postsynaptic function and intrinsic excitability, while vlPAG-GABA showed increased intrinsic excitability and reduced presynaptic inhibition. Therefore, these findings strongly suggest that RIH simultaneously excites vlPAG-Glu and vlPAG-GABA neurons, the final behavioral output depends on the relative balance of the activities of these two types of neurons. Artificial activation of vlPAG-Glu or inhibition of vlPAG-GABA can effectively alleviate hypersensitivity behavior. This study provides new ideas and theoretical basis for clinical intervention strategies for RIH.

Cocaine and methamphetamine use disorders pose public health concerns due to the high propensity for relapse driven by persistent drug-associated memories. Output from the medial prefrontal cortex (mPFC) regulates relapse and is controlled by parvalbumin (PV) interneurons, which are surrounded by perineuronal nets (PNNs) that support precise PV neuron firing. We previously showed that removal of mPFC PNNs, which reduces PV firing, disrupted reconsolidation of a cocaine self-administration memory when rats were given a novel, but not familiar, memory retrieval session. Ketamine rapidly suppresses PV neuron output, so we tested whether a single low dose (6 mg/kg) administered before or after a familiar or novel memory retrieval session altered cocaine cue reinstatement. Ketamine given prior to the novel, but not familiar, retrieval session reduced cue reinstatement in male Sprague-Dawley rats. In addition, both ketamine treatments combined with a novel retrieval session reduced PNN intensity around PV neurons after cue reinstatement, suggesting that PNN decreases may be unrelated to reinstatement. However, ketamine reduced the number of c-Fos-activated PV neurons immediately after the novel memory retrieval session, indicating that ketamine may reduce reinstatement through reduced PV neuron function at the time of memory retrieval. Ketamine given just prior to a novel memory retrieval session also reduced cue-induced reinstatement in rats trained for methamphetamine, but not fentanyl or sucrose self-administration. Collectively, these studies show that a single, low dose of ketamine combined with a novel memory retrieval reduces psychostimulant-seeking behavior, and may help delineate the mechanisms for ketamine-reduced relapse in psychostimulant use disorders.

Migraine is the most common disabling primary headache disorder. However, currently available therapies for migraine pain are still limited. In the present study, we investigated the effects of gut microbiome perturbation and synbiotics supplementation on migraine-like pain in male mice and explored the underlying mechanism. We observed that the supplementation with synbiotics inhibited Broad-spectrum antibiotics (ABX)-prolonged migraine-like pain. Using 16S rRNA sequencing, we analyzed bacterial composition and abundance in the mouse gut, and we found that the supplementation with synbiotics recovered ABX-reduced Bacteroidota, which produces acetate and propionate in the gut, and such supplementation increased the levels of short-chain fatty acids (SCFAs) in the gut. SCFAs, specifically acetate and propionate, reversed the ABX-caused prolongation of migraine-like pain. We further found that ABX treatment decreased the expression of SCFA receptors in the gut and the supplementation with synbiotics restored the expression of SCFA receptor FFAR2, but not FFAR3, in the gut. Moreover, genetic deletion of FFAR2 in the Ffar2 knockout mice blocked the effect of synbiotics on migraine-like pain. Our results suggest that gut microbiome perturbation contributes to the prolongation of migraine-like pain and synbiotics can inhibit such pain prolongation by recovering disturbed gut microbiome and restoring SCFAs-FFAR2 signaling.