Neuropharmacology最新文献

Glioblastoma multiforme (GBM) is the most common primary intracranial tumor with characteristics of high aggressiveness and poor prognosis. Deguelin, a component from the bark of Leguminosae Mundulea sericea (African plant), displays antiproliferative effects in some tumors, however, the inhibitory effect and mechanism of deguelin on GBM were still poorly understood. At first, we found that deguelin reduced the viability of GBM cells by causing cell cycle arrest in G2/M phase and inducing their apoptosis. Secondly, deguelin inhibited the migration of GBM cells. Next, RNA-seq analysis identified that CCL2 (encoding chemokine CCL2) was downregulated significantly in deguelin-treated GBM cells. As reported, CCL2 promoted the cell growth, and CCL2 was associated with regulating NFκB signaling pathway, as well as involved in modulating tumor microenvironment (TME). Furthermore, we found that deguelin inactivated CCL2/NFκB signaling pathway, and exougous CCL2 could rescue the anti-inhibitory effect of deguelin on GBM cells via upregulating NFκB. Finally, we established a syngeneic intracranial orthotopic GBM model and found that deguelin regressed the tumor growth, contributed to an anti-tumorigenic TME and inhibited angiogenesis of GBM by suppressing CCL2/NFκB in vivo. Taken together, these results suggest the anti-GBM effect of deguelin via inhibiting CCL2/NFκB pathway, which may provide a new strategy for the treatment of GBM.

Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca²⁺ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca²⁺-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7–10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure.

Clinical evidence suggests that early malnutrition promotes symptoms related to psychiatric disorders later in life. Nevertheless, the molecular mechanisms underpinning nutritional injury induce depression remains unknown. The purpose of the present study was to evaluate whether perinatal protein restriction increases vulnerability to developing depressive-like behavior in adulthood by focusing on anhedonia, a core symptom of depression. To this, male adult Wistar rats submitted to a protein restriction schedule at perinatal age (PR-rats), were subjected to the sucrose preference test (SPT), the novel object recognition test (NORT), the forced swim test (FST), and the elevated plus maze (EPM), and compared to animals fed with a normoprotein diet. To investigate neurobiological substrates linked to early protein undernutrition-facilitated depressive-like behavior, we assessed the levels of brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the nucleus accumbens (NAc), and evaluated the reversal of anhedonic-like behavior by infusing ANA-12. We found that early malnutrition decreased sucrose preference, impaired performance in the NORT and increased immobility time in the FST. Furthermore, perinatal protein-restriction-induced anhedonia correlated with increased BDNF and p-TrkB protein levels in the NAc, a core structure in the reward circuit linked with anhedonia. Finally, bilateral infusion of the TrkB antagonist ANA-12 into the NAc shell ameliorated a reduced sucrose preference in the PR-rats.

Altogether, these findings revealed that protein restriction during pregnancy and lactation facilitates depressive-like behavior later in life and may increase the risk of developing anhedonia by altering BDNF-TrkB in the NAc shell.

Aging is characterized by a functional decline in several physiological systems. α-Klotho-hypomorphic mice (Kl^−/−) exhibit accelerated aging and cognitive decline. We evaluated whether male and female α-Klotho-hypomorphic mice show changes in the expression of synaptic proteins, N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, postsynaptic density protein 95 (PSD-95), synaptophysin and synapsin, and the activity of Na⁺, K⁺-ATPase (NaK) isoforms in the cerebellum and hippocampus. In this study, we demonstrated that in the cerebellum, Kl^−/− male mice have reduced expression of GluA1 (AMPA) compared to wild-type (Kl^+/+) males and Kl^−/− females. Also, Kl−/− male and female mice show reduced ɑ2/ɑ3-NaK and Mg²⁺-ATPase activities in the cerebellum, respectively, and sex-based differences in NaK and Mg²⁺-ATPase activities in both the regions. Our findings suggest that α-Klotho could influence the expression of AMPAR and the activity of NaK isoforms in the cerebellum in a sex-dependent manner, and these changes may contribute, in part, to cognitive decline.

Traumatic brain injuries (TBI) of varying severity are becoming more frequent all over the world. The process of neuroinflammation, in which macrophages and microglia are key players, underlies all types of brain damage. The present study focuses on evaluating the therapeutic potential of N-docosahexaenoylethanolamine (DHEA, synaptamide), which is an endogenous metabolite of docosahexaenoic acid in traumatic brain injury. Previously, several in vitro and in vivo models have shown significant anti-neuroinflammatory and synaptogenic activity of synaptamide. The results of the present study show that synaptamide by subcutaneous administration (10 mg/kg/day, 7 days) exerts anti-inflammatory and anti-apoptotic effects in the thalamus and cerebral cortex of experimental animals (male C57BL/6 mice). Were analyzed the dynamics of changes in the activity of Iba-1- and CD68-positive microglia/macrophages, the level of production of pro-inflammatory cytokines (IL1β, IL6, TNFα) and pro-apoptotic proteins (Bad, Bax), the expression of pro- and anti-inflammatory markers (CD68, CD206, arg-1). ATF3 transcription factor distribution and neuronal state in the thalamus and cerebral cortex of animals with craniotomy, traumatic brain injury, and therapy are quantitatively assessed. The obtained data showed that synaptamide: (1) has no effect on the total pool of microglia/macrophages; (2) inhibits the activity of pro-inflammatory microglia/macrophages and cytokines they produce; (3) increases the expression of CD206 but not arg-1; (4) has anti-apoptotic effect and (5) improves the morphological state of neurons. The results obtained confirm the high therapeutic potential of synaptamide in the therapy of traumatic brain injury.

Stress is a major risk factor for several neuropsychiatric disorders in women, including postpartum depression. During the postpartum period, diminished ovarian hormone secretion increases susceptibility to developing depressive symptoms. Pleiotropic peptide hormones, like prolactin, are markedly released during lactation and suppress hypothalamic-pituitary-adrenal axis responses in women and acute stress-induced behavioral responses in female rodents. However, the effects of prolactin on chronic stress-induced maladaptive behaviors remain unclear. Here, we used chronic variable stress to induce maladaptive physiology in ovariectomized female rats and concurrently administered prolactin to assess its effects on several depression-relevant behavioral, endocrine, and neural characteristics. We found that chronic stress increased sucrose anhedonia and passive coping in saline-treated, but not prolactin-treated rats. Prolactin treatment did not alter stress-induced thigmotaxis, corticosterone (CORT) concentrations, hippocampal cell activation or survival. However, prolactin treatment reduced basal CORT concentrations and increased dopaminergic cells in the ventral tegmental area. Further, prolactin-treated rats had reduced microglial activation in the ventral hippocampus following chronic stress exposure. Together, these data suggest prolactin mitigates chronic stress-induced maladaptive behaviors and physiology in hypogonadal females. Moreover, these findings imply neuroendocrine-immune mechanisms by which peptide hormones confer stress resilience during periods of low ovarian hormone secretion.

Neurological disorders pose a huge worldwide challenge to the healthcare system, necessitating innovative strategies for targeted drug delivery to the central nervous system. Alzheimer's disease (AD) is an untreatable neurodegenerative condition characterized by dementia and alterations in a patient's physiological and mental states. Since ancient times, medicinal plants have been an important source of bioactive phytochemicals with immense therapeutic potential. This review investigates new and safer alternatives for prevention and treatment of disease related to inevitable side effects associated with synthetic compounds. This review examines how nanotechnology can help in enhancing the delivery of neuroprotective phytochemicals in AD. Nevertheless, despite their remarkable neuroprotective properties, these natural products often have poor therapeutic efficacy due to low bioavailability, limited solubility and imperfect blood brain barrier (BBB) penetration. Nanotechnology produces personalized drug delivery systems which are necessary for solving such problems. In overcoming these challenges, nanotechnology might be employed as a way forward whereby customized medication delivery systems would be established as a result. The use of nanocarriers in the design and application of important phytochemicals is highlighted by this review, which indicate potential for revolutionizing neuroprotective drug delivery. We also explore the complications and possibilities of using nanocarriers to supply nutraceuticals and improve patients' standard of living, and preclinical as well as clinical investigations displaying that these techniques are effective in mitigating neurodegenerative diseases. In order to fight brain diseases and improve patient's health, scientists and doctors can employ nanotechnology with its possible therapeutic interventions.

Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors (GPCRs) that are activated by the endogenous neurotransmitter, acetylcholine (ACh). Disruption of mAChR signalling has been associated with a variety of neurological disorders and non-neurological diseases. Consequently, the development of agonists and antagonists of the mAChRs has been a major avenue in drug discovery. Unfortunately, mAChR ligands are often associated with on-target side effects for two reasons. The first reason is due to the high sequence conservation at the orthosteric ACh binding site among all five receptor subtypes (M₁-M₅), making on-target subtype selectivity a major challenge. The second reason is due to on-target side effects of mAChR drugs that are associated with the pleiotropic nature of mAChR signalling at the level of a single mAChR subtype. Indeed, there is growing evidence that within the myriad of signalling events produced by mAChR ligands, some will have therapeutic benefits, whilst others may promote cholinergic side effects. This paradigm of drug action, known as ligand bias or biased agonism, is an attractive feature for next-generation mAChR drugs, as it holds the promise of developing drugs devoid of on-target adverse effects. Although relatively simple to detect and even quantify in vitro, ligand bias, as observed in recombinant systems, does not always translate to in vivo systems, which remains a major hurdle in GPCR drug discovery, including the mAChR family. Here we report recent studies that have attempted to detect and quantify ligand bias at the mAChR family, and briefly discuss the challenges associated with biased agonist drug development.

This article is part of the Special Issue on “Ligand Bias”.