Hydroxyl carboxylic acid receptor-2 (HCAR2) as a potential target in neurometabolic diseases.

Hydroxycarboxylic acid receptor 2 (HCAR2) is a G-protein-coupled receptor initially identified for its role in lipid metabolism. Beyond its classical metabolic functions, HCAR2 plays a pivotal role in chronic inflammatory diseases, neurometabolic disorders, and pain modulation. Evidence from preclinical studies suggest that when endogenously activated by β-hydroxybutyrate and pharmacologically by niacin and its derivatives, HCAR2 attenuates microglial reactivity, suppress pro-inflammatory cytokine release, and modulate neuronal excitability, by offering neuroprotective benefits in neurological disorders and chronic pain.

Modulatory activity of N-palmitoyl-D-glucosamine in bridging gut dysbiosis and pain mechanisms.

Gut dysbiosis, characterized by an imbalance in the composition and function of microbiota, has emerged as a critical factor in the regulation of pain transmission and behavior through the gut-brain axis. When dysbiosis occurs, these regulatory functions are disrupted, leading to systemic inflammation and altered signaling at central nervous system. In this study, we examined the therapeutic potential of palmitoyl glucosamine (PGA), a fatty acid amide with sharp anti-inflammatory properties, in a gut dysbiosis condition induced by antibiotic exposure in male mice.

Impact of Type 1 Diabetes on Testicular Microtubule Dynamics, Sperm Physiology, and Male Reproductive Health in Rat.

Type 1 diabetes (T1D) is a chronic metabolic disease defined by sustained hyperglycemia, leading to oxidative stress (OS) and systemic complications, including male subfertility. This study investigates the potential impact of T1D-induced OS on microtubule (MTs) dynamics and microtubule-associated proteins (MAPs) in the testis and spermatozoa (SPZ). Using a streptozotocin-induced T1D rat model, we examined the expression and localization of key MAPs, including Microtubule Affinity-Regulating Kinase 4 (MARK4), Microtubule-Associated Protein 1A (MAP1A), Dynein Light Chain LC8-Type 1 (DYNLL1), Prolyl Endopeptidase (PREP), and Radial Spoke Head 6 Homolog A (RSPH6A), alongside sperm functional parameters.

Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat.

Background: The CXC motif chemokine ligand 8 (CXCL8)-CXC motif chemokine receptor 1/2 (CXCR1/2) axis has been implicated in type 1 diabetes mellitus (T1DM). Its actions on non-immune cells may also contribute to T1DM-associated complications, including painful diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR).

Methods: We assessed the efficacy of early (4-8 weeks) or late (8-12 weeks) daily ladarixin (LDX) for the treatment of streptozotocin (STZ)-induced T1DM and the related complications of DPN or DR in male rats.

Enhanced visualization of endocannabinoids spatial distribution in mouse brain via MALDI-2 mass spectrometry imaging.

Endocannabinoids (eCBs) are endogenous lipid messengers that primarily bind cannabinoid receptors CB/CB and together with the enzymes that regulate their biosynthesis and degradation define the endocannabinoid system. The eCB signaling system plays a key role in the central nervous system, and results often altered in neurological disorders. The analysis of eCBs is challenging due to their low concentration in biospecimens, and this is exacerbated in Mass Spectrometry Imaging (MSI) where low sensitivity and tissue dependent ion suppression obscure their spatial visualization.

Combining and extracts: a novel pharmacological approach in inflammatory vestibulodynia.

Vulvodynia is a chronic pain condition that affects the vulvar area, often resulting in significant discomfort and a reduced quality of life. Current treatments for vulvodynia are limited, and there is a need for more effective therapeutic options. Acmella oleracea, known for its spilanthol content, and Boswellia serrata, rich in boswellic acids, have been explored for their potential analgesic properties in pain management.

Acute kappa opioid receptor blocking disrupts the pro-cognitive effect of cannabidiol in neuropathic rats.

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.

Identification of Cannabidiolic and Cannabigerolic Acids as MTDL AChE, BuChE, and BACE-1 Inhibitors Against Alzheimer's Disease by In Silico, In Vitro, and In Vivo Studies.

Cannabidiolic (CBDA) and cannabigerolic (CBGA) acids are naturally occurring compounds from Cannabis sativa plant, previously identified by us as dual PPARα/γ agonists. Since the development of multitarget-directed ligands (MTDL) represents a valuable strategy to alleviate and slow down the progression of multifactorial diseases, we evaluated the potential ability of CBDA and CBGA to also inhibit enzymes involved in the modulation of the cholinergic tone and/or β-amyloid production. A multidisciplinary approach based on computational and biochemical studies was pursued on selected enzymes, followed by behavioral and electrophysiological experiments in an AD mouse model.

Corrigendum: Long-term efficacy and reduced side-effects of buprenorphine in patients with moderate and severe chronic pain.

[This corrects the article DOI: 10.3389/fphar.2024.

The influence of glutamate receptors on insulin release and diabetic neuropathy.

Diabetes causes macrovascular and microvascular complications such as peripheral neuropathy. Glutamate regulates insulin secretion in pancreatic β-cells, and its increased activity in the central nervous system is associated with peripheral neuropathy in animal models of diabetes. One strategy to modulate glutamatergic activity consists in the pharmacological manipulation of metabotropic glutamate receptors (mGluRs), which, compared to the ionotropic receptors, allow for a fine-tuning of neurotransmission that is compatible with therapeutic interventions.

Long-term efficacy and reduced side-effects of buprenorphine in patients with moderate and severe chronic pain.

Background: Chronic pain significantly impacts quality of life and poses substantial public health challenges. Buprenorphine, a synthetic analog of thebaine, is recognized for its potential in managing moderate to severe chronic pain with fewer side effects and a lower incidence of tolerance compared to traditional opioids.

Objective: This retrospective study aimed to assess the long-term efficacy and safety of buprenorphine transdermal patches in patients with moderate and severe chronic pain, with a focus on pain relief sustainability and tolerance development.

A 'double-edged' role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs.

We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic, and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity. Systemic treatment of alloswitch-1, an intrinsically active mGlu5 receptor NAM, caused analgesia, and the effect was reversed by light-induced drug inactivation in the prelimbic and infralimbic cortices, and thalamus.

Early biomarkers in the presymptomatic phase of cognitive impairment: changes in the endocannabinoidome and serotonergic pathways in Alzheimer's-prone mice after mTBI.

Background: Despite extensive studies on the neurobiological correlates of traumatic brain injury (TBI), little is known about its molecular determinants on long-term consequences, such as dementia and Alzheimer's disease (AD).

Methods: Here, we carried out behavioural studies and an extensive biomolecular analysis, including inflammatory cytokines, gene expression and the combination of LC-HRMS and MALDI-MS Imaging to elucidate the targeted metabolomics and lipidomics spatiotemporal alterations of brains from wild-type and APP-SWE mice, a genetic model of AD, at the presymptomatic stage, subjected to mild TBI.

Results: We found that brain injury does not affect cognitive performance in APP-SWE mice.

Type 1 diabetes impairs the activity of rat testicular somatic and germ cells through NRF2/NLRP3 pathway-mediated oxidative stress.

Background: It is well known that metabolic disorders, including type 1 diabetes (T1D), are often associated with reduced male fertility, mainly increasing oxidative stress and impairing the hypothalamus-pituitary-testis (HPT) axis, with consequently altered spermatogenesis and reduced sperm parameters. Herein, using a rat model of T1D obtained by treatment with streptozotocin (STZ), we analyzed several parameters of testicular activity.

Methods: A total of 10 adult male Wistar rats were divided into two groups of five: control and T1D, obtained with a single intraperitoneal injection of STZ.

Cannabidiol in the dorsal hippocampus attenuates emotional and cognitive impairments related to neuropathic pain: The role of prelimbic neocortex-hippocampal connections.

Background And Purpose: Chronic neuropathic pain (NP) is commonly associated with cognitive and emotional impairments. Cannabidiol (CBD) presents a broad spectrum of action with a potential analgesic effect. This work investigates the CBD effect on comorbidity between chronic NP, depression, and memory impairment.

PEA-OXA restores cognitive impairments associated with vitamin D deficiency-dependent alterations of the gut microbiota.

There is a growing evidence suggesting the association of vitamin D deficiency (VDD) and cognitive impairment. In this study we evaluated the possible involvement of gut microbiota in the cognitive impairments mediated by VDD and investigated the effects of pharmacological treatment with the oxazoline derivative of the aliamide palmitoylethanolamide, 2-Pentadecyl-2-oxazoline (PEA-OXA). Mice were submitted to behavioural, biochemical and electrophysiological analysis to assess whether their vitamin D status affected cognitive performance together with gut microbiota composition.

Spinal neuronal activity and neuroinflammatory component in a mouse model of CFA-induced vestibulodynia.

Vestibulodynia is a complex pain disorder characterized by chronic discomfort in the vulvar region, often accompanied by tactile allodynia and spontaneous pain. In patients a depressive behaviour is also observed. In this study, we have used a model of vestibulodynia induced by complete Freund's adjuvant (CFA) focusing our investigation on the spinal cord neurons and microglia.

Novel pyrrole based CB2 agonists: New insights on CB2 receptor role in regulating neurotransmitters' tone.

The cannabinoid system is one of the most investigated neuromodulatory systems because of its involvement in multiple pathologies such as cancer, inflammation, and psychiatric diseases. Recently, the CB2 receptor has gained increased attention considering its crucial role in modulating neuroinflammation in several pathological conditions like neurodegenerative diseases. Here we describe the rational design of pyrrole-based analogues, which led to a potent and pharmacokinetically suitable CB2 full agonist particularly effective in improving cognitive functions in a scopolamine-induced amnesia murine model.

Novel Dual-Acting Hybrids Targeting Type-2 Cannabinoid Receptors and Cholinesterase Activity Show Neuroprotective Effects In Vitro and Amelioration of Cognitive Impairment In Vivo.

Alzheimer's disease (AD) is a neurodegenerative form of dementia characterized by the loss of synapses and a progressive decline in cognitive abilities. Among current treatments for AD, acetylcholinesterase (AChE) inhibitors have efficacy limited to symptom relief, with significant side effects and poor compliance. Pharmacological agents that modulate the activity of type-2 cannabinoid receptors (CB2R) of the endocannabinoid system by activating or blocking them have also been shown to be effective against neuroinflammation.

Affective and Cognitive Impairments in Rodent Models of Diabetes.

Diabetes and related acute and long-term complications have a profound impact on cognitive, emotional, and social behavior, suggesting that the central nervous system (CNS) is a crucial substrate for diabetic complications. When anxiety, depression, and cognitive deficits occur in diabetic patients, the symptoms and complications related to the disease worsen, contributing to lower quality of life while increasing health care costs and mortality. Experimental models of diabetes in rodents are a fundamental and valuable tool for improving our understanding of the mechanisms underlying the close and reciprocal link between diabetes and CNS alterations, including the development of affective and cognitive disorders.

Exploitation of Autophagy Inducers in the Management of Dementia: A Systematic Review.

The social burden of dementia is remarkable since it affects some 57.4 million people all over the world. Impairment of autophagy in age-related diseases, such as dementia, deserves deep investigation for the detection of novel disease-modifying approaches.

A "double-edged" role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs.

Knowing the site of drug action is important to optimize effectiveness and address any side effects. We used light-sensitive drugs to identify the brain region-specific role of mGlu5 metabotropic glutamate receptors in the control of pain. Optical activation of systemic JF-NP-26, a caged, normally inactive, negative allosteric modulator (NAM) of mGlu5 receptors, in cingulate, prelimbic and infralimbic cortices and thalamus inhibited neuropathic pain hypersensitivity.

Combination Drug Therapy for the Management of Chronic Neuropathic Pain.

Chronic neuropathic pain (NP) is an increasingly prevalent disease and leading cause of disability which is challenging to treat. Several distinct classes of drugs are currently used for the treatment of chronic NP, but each drug targets only narrow components of the underlying pathophysiological mechanisms, bears limited efficacy, and comes with dose-limiting side effects. Multimodal therapies have been increasingly proposed as potential therapeutic approaches to target the multiple mechanisms underlying nociceptive transmission and modulation.