Neuropharmacology最新文献

Migraine is a highly prevalent neurological disorder. Alpha-asarone (ASA), a major active component found in Acorus tatarinowii, plays a crucial role in analgesia and anti-inflammation for neuropathic pain. This study aimed to assess the efficacy of ASA against migraine and elucidate its potential mechanisms using a well-established inflammatory soup (IS) migraine female rat model. Mechanical pain thresholds were assessed daily before IS infusion, followed by post-infusion administration of ASA. Subsequently, spontaneous locomotor activities, exploratory behavior, short-term spatial memory, and photophobia were blindly evaluated after the final drug administration. The rats were then sacrificed for investigation into the underlying mechanisms of action. Network pharmacology was also employed to predict potential targets and pathways of ASA against migraine. The anti-inflammatory activity of ASA and pathway-related proteins were examined in BV2 cells stimulated with lipopolysaccharides (LPS). The results demonstrated that ASA ameliorated cutaneous hyperalgesia and photophobia while improving spatial memory and increasing exploratory behavior in IS rats. ASA attenuated central sensitization-related indicators and excessive glutamate levels while enhancing GABA synthesis. ASA rescued neuronal loss in the cortex and hippocampus of IS rats. Notably, the ability of ASA to improve spatial memory performance in the Y maze test was not observed with sumatriptan, a first-line treatment drug, suggesting the potential involvement of the TLR4 pathway. Moreover, ASA suppressed microglial activation, reduced pro-inflammatory factors, and downregulated TLR4, MyD88, p–NF–κB/NF-κB, NLRP3, caspase-1, IL-1β, and IL-18. Overall, ASA demonstrated its potential to alleviate hyperalgesia and improve behavioral performance in migraine rats by inhibiting hyperexcitability and microglia-related inflammation.

With the current unmet demand for effective pain relief, analgesics without major central adverse effects are highly appealing, such as peripherally restricted kappa-opioid receptor (KOR) agonists. In this study, Conorphin-66, an analog of the selective KOR peptide agonist Conorphin T, was pharmacologically characterized in a series of experiments, with CR845 serving as the reference compound. Firstly, in vitro functional assay indicated that Conorphin-66 selectively activates KOR and exhibits weak β-arrestin2 signaling bias (−1.54 versus −4.35 for CR845). Additionally, subcutaneous Conorphin-66 produced potent antinociception in mouse pain models with ED₅₀ values ranged from 0.02 to 3.28 μmol/kg, including tail-flick test, post-operative pain, formalin pain, and acetic acid-induced visceral pain. Similarly, CR845 exert potent antinociception in mouse pain models ranged from 0.15 to 1.47 μmol/kg. Notably, antagonism studies revealed that the analgesic effects of Conorphin-66 were mainly mediated by the peripheral KOR. Furthermore, Conorphin-66 produced non-tolerance-forming antinociception over 8 days. Unlike CR845, subcutaneous Conorphin-66 did not promote the sedation, anxiogenic effects, depressive-like effects, but did exhibit diuretic activity. Further study showed that Conorphin-66 does not have apparent antipruritic effects in an acute itch model. Overall, Conorphin-66 emerges as a novel peripherally restricted KOR agonist that produced potent antinociception with reduced side effects.

Objective

Stigma can create divisions within societies, hindering social cohesion and cooperation. Notably, it has significant public health implications, especially during infectious disease outbreaks like COVID-19. However, little is known about the neural and molecular basis of disease-related stigma and their association with individual differences.

Methods

To address this gap, we performed a double-blind, placebo-controlled, within-subject design study with 70 males, to investigate the effect of intranasal oxytocin (OT) administration on the explicit and implicit processing of disease-related stigma (i.e., COVID-19 stigma). After self-administrated 24 IU of OT or placebo, participants completed a stigma evaluation task and an Implicit Association Test (IAT) to assess the explicit and implicit processes of stigma evaluation, respectively.

Results

The results showed that oxytocin amplified the differences between participants with high and low social anxiety in explicit COVID-19 stigma, with a higher inclination to attribute the stigmatized status of the stigmatized targets (i.e., COVID-19 related group) to personal causes in high social anxiety individuals, but reduced blame towards the stigmatized targets in low social anxiety individuals under oxytocin compared to placebo treatment. Furthermore, oxytocin strengthened the connections between responsibility attribution and the other processes (i.e., emotional, approach motivation, social deviance). While no modulation of oxytocin on implicit stigma emerged, oxytocin did modulate the associations between specific dimensions of explicit stigma (i.e., social deviance and approach motivation) and implicit stigma.

Conclusion

In conclusion, these findings demonstrated that intranasal oxytocin administration could temporally impact the explicit cognitive judgment in disease-related stigma but not the implicit aspect; furthermore, it modulated in distinct ways in individuals with different levels of social anxiety. These findings highlight the trait-dependent oxytocin modulation on disease-related stigma, implying that oxytocin is partly involved in the endocrine system of disease-related stigma. By unraveling the molecular basis of stigma and its association with individual traits, such as social anxiety, we can tailor interventions to meet specific needs of different individuals in the future.

Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aβ), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 μM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aβ by −69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by −33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by −25%, (iv) diminishes oxidized DJ-1 at Cys106-SO₃ by −29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by −33, −86, and −78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca²⁺ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aβ (Vina Score −6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca²⁺ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

When a naïve observer meets with a familiar conspecific in pain, mice may have a myriad of social (sniffing, allolicking, allogrooming, huddling) and non-social (self-grooming) behaviors under dyadic social interaction (DSI) paradigm. Unlike male, female observers express more allolicking behavior toward injury site of a familiar female in pain, but with less body allogrooming. In current study, we investigated roles of natural estrus cycle phases and ovarian estrogen in these behaviors and results showed that: (1) there was no changes in above behaviors in terms of latency, time and bouts across different natural estrus cycle phases in intact female. (2) however, ovariectomy (OVX) changed estrus cycle phases, lowered circulating level of ovarian estrogen, reduced time and bouts of allolicking behavior and increased time of self-grooming without affecting other behaviors. Moreover, OVX in observers decreased social buffering effect of DSI on spontaneous pain-related behavior in demonstrator relative to naïve and sham controls. (3) treatment of OVX-female with β-estradiol (E₂) or progesterone (PROG) as replacement therapies, only E₂ reversed impairment of allolicking behavior. (4) Additionally, socially transferred pain could be identified in intact female across all estrus cycle phases post-DSI, but disappeared in OVX-female, which could be reversed completely by E₂ but not by PROG. (5) Finally, serum levels of estrogen, PROG, oxytocin, arginine vasopressin (AVP), prolactin, norepinephrine and 5-HT were examined by ELISA after E₂, results showed only AVP level was significantly increased. These results suggest both injury site-targeted caring behavior and socially transferred pain are selectively dependent on ovarian estrogen.

Background and aims

Neuropathic pain (NP) has a high incidence in the general population, is closely related to anxiety disorders, and has a negative impact on the quality of life. Cannabidiol (CBD), as a natural product, has been extensively studied for its potential therapeutic effects on symptoms such as pain and depression (DP). However, the mechanism of CBD in improving NP with depression is not fully understood.

Methods

First, we used bioinformatics tools to deeply mine the intersection genes associated with NP, DP, and CBD. Secondly, the core targets were screened by Protein-protein interaction network, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, molecular docking and molecular dynamics simulation. Next, the effects of CBD intervention on pain and depressive behaviors in the spinal nerve ligation (SNL) mouse model were evaluated using behavioral tests, and dose-response curves were plotted. After the optimal intervention dose was determined, the core targets were verified by Western blot (WB) and Quantitative Polymerase Chain Reaction (qPCR). Finally, we investigated the potential mechanism of CBD by Nissl staining, Immunofluorescence (IF) and Transmission Electron Microscopy (TEM).

Results

A total of five core genes of CBD most associated with NP and DP were screened by bioinformatics analysis, including PTGS2, GPR55, SOD1, CYP1A2 and NQO1. Behavioral test results showed that CBD by intraperitoneal administration 5 mg/kg can significantly improve the pain behavior and depressive state of SNL mice. WB, qPCR, IF, and TEM experiments further confirmed the regulatory effects of CBD on key molecules.

Conclusion

In this study, we found five targets of CBD in the treatment of NP with DP. These findings provide further theoretical and experimental basis for CBD as a potential therapeutic agent.

Despite increasing recognition that there is a neurobiological basis of antisocial behavior in addition to its psychosocial foundation, much less is known about the specificity of the neurobiological findings to the psychiatric condition of antisocial personality disorder (APD). This article provides a review of research on genetic, brain imaging, neurocognitive, and psychophysiological factors in relation to assessments of APD. Findings show that there are significant genetic effects on APD, particularly related to the serotonergic system, as well as abnormalities in brain regions such as the frontal lobe. Associations between psychophysiological measures of autonomic nervous system functioning and APD are more mixed. Results indicating that APD has a significant genetic basis and is characterized by abnormalities in brain structure/function and neurocognitive impairments provide additional evidence that supports the conceptualization of APD as a neurodevelopmental disorder. Findings may also help inform treatment approaches that target neurobiological risks for APD symptoms.

Studies have indicated that the human brain exhibits a more robust neural empathic response towards individuals of the same racial ingroup than those of the outgroup. However, the impact of the oxytocinergic system on the dynamic connectivity between brain regions involved in racial ingroup bias in empathy (RIBE) and its implications for real-life social interaction intention remains unclear. To address this gap, we employed functional magnetic resonance imaging (fMRI) to investigate RIBE-modulated neural activities and the influence of the oxytocinergic system at both neural and behavioral levels. Participants homozygous for the A/A and G/G genotypes of the oxytocin receptor gene (OXTR) rs53576 polymorphism underwent scanning while making judgments about painful versus non-painful stimuli in same-race versus other-race scenarios following either oxytocin (OT) or placebo treatment. The results revealed greater activity in the anterior cingulate cortex (ACC) and anterior insula (AI) in response to same-race compared to other-race models in the G/G group but not in the A/A group. RIBE also modulated the connections between bilateral AI and the ACC, and the effect of OT on this modulatory effect was moderated by genotype rs53576 and interpersonal trust. Moreover, more extensive changes in AI-ACC connections were associated with higher levels of revenge intention in the low interpersonal trust group. Overall, our findings suggest a pivotal role of the oxytocinergic system in the RIBE-modulated neural activities and revenge intention in human interactions with the modulatory effect of interpersonal trust.

Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs. We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain. Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia. Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation. Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology.

Cognitive dysfunction is an important comorbidity of type 2 diabetes mellitus (T2DM). Sodium butyrate (NaB) is a short-chain fatty acid and has an effect improving T2DM-associated cognitive dysfunction. Using a high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mouse model, the present study investigated the mechanism involved in the beneficial effect of butyrate on diabetic cognitive dysfunction, with a focus on ameliorating mitochondrial damage through regulating the adenosine monophosphate-activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1α (AMPK/PGC-1α) pathway considering the important role of mitochondrial impairments in the occurrence of T2DM-associated cognitive dysfunction. We found, based on reconfirmation of the improvement of NaB on cognitive impairment, that NaB treatment improved damaged synaptic structural plasticity including the decrease in dendritic spine density and downregulation in the expression of postsynaptic density protein 95 and synaptophysin in the hippocampus in the model mice. NaB treatment also ameliorated mitochondrial ultrastructural damage, increased mitochondrial membrane potential and adenosine 5′-triphosphate content, and improved mitochondrial biogenesis and dynamics in the model mice. Furthermore, the expression of phosphorylated AMPK and PGC-1α was upregulated after NaB treatment in the model mice. In particular, the above beneficial effects of NaB were blocked by the inhibition of either AMPK or PGC-1α. In conclusion, NaB treatment improved cognitive impairment and damaged synaptic structural plasticity in the hippocampus by ameliorating damage to mitochondrial morphology and function through regulating the AMPK/PGC-1α pathway in HFD/STZ-induced T2DM mice.