Immune-microbiome interplay and its implications in neurodegenerative disorders.

The neurodegeneration and its related CNS pathologies need an urgent toolbox to minimize the global mental health burden. The neuroimmune system critically regulates the brain maturation and survival of neurons across the nervous system. The chronic manipulated immunological drive can accelerate the neuronal pathology hence promoting the burden of neurodegenerative disorders. The gut is home for trillions of microorganisms having a mutual relationship with the host system. The gut-brain axis is a unique biochemical pathway through which the gut residing microbes connects with the brain cells and regulates various physiological and pathological cascades. The gut microbiota and CNS communicate using a common language that synchronizes the tuning of immune cells. The intestinal gut microbial community has a profound role in the maturation of the immune system as well as the development of the nervous system. We have critically summarised the clinical and preclinical reports from the past a decade emphasising that the significant changes in gut microbiota can enhance the host susceptibility towards neurodegenerative disorders. In this review, we have discussed how the gut microbiota-mediated immune response inclines the host physiology towards neurodegeneration and indicated the gut microbiota as a potential future candidate for the management of neurodegenerative disorders.

Epigallocatechin-3-gallate improves chronic alcohol-induced cognitive dysfunction in rats by interfering with neuro-inflammatory, cell death and oxido-nitrosative cascade.

Alcohol consumption for a longer period of time is linked with neuronal damage and an increase in inflammatory signaling resulting in cell death and dementia. Natural compounds are the focus of research due to their high efficacy and good safety profile. Here we have investigated the effect of chronic epigallocatechin-3-gallate (EGCG) administration against the alcohol-induced cognitive deficit rats. Male Wistar rats were exposed to the 12% ethanol (10 g/kg; oral gavage) for ten weeks and treated with EGCG (25, 50, and 100 mg/kg) for the same duration. Ethanol exposure led to the impaired spatial memory and learning in rats assessed using the Morris water maze and elevated plus-maze test. Further, we assessed the role of EGCG in mitigating the oxidative stress, neuroinflammatory and cell death signaling associated markers. Co-administration with EGCG significantly prevented all the behavioral, biochemical and molecular alterations in the different brain regions of ethanol-treated rats in a dose-dependent manner. EGCG suppressed the acetylcholinesterase activity, increased oxidative-nitrosative stress, cytokines (TNF-alpha and IL-1beta), NF-kappa ß and caspase-3 levels in both the cortex and hippocampus of ethanol-treated rats. Our preliminary study demonstrated that EGCG improves the oxido-nitrosative stress, inflammation, and cell death signaling associated with ethanol-induced cognitive dysfunction. This suggests the potential role of EGCG in mitigating the cognitive deficits associated with chronic alcohol consumption.

Targeting human Mas-related G protein-coupled receptor X1 to inhibit persistent pain.

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1 This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated Ca2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.

Peripherally Acting µ-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats.

BACKGROUND: Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin [D-Arg2, Lys4] (1-4) amide, a peripherally acting µ-opioid receptor agonist, attenuates ongoing pain-associated manifestations after nerve injury in rats and mice. METHODS: Using conditioned place preference assay, the authors tested whether animals show a preference to the environment associated with drug treatment. Wide-dynamic range and dorsal root ganglion neuronal activities were measured by electrophysiology recording and calcium imaging. RESULTS: Nerve-injured animals stayed longer in dermorphin [D-Arg2, Lys4] (1-4) amide-paired chamber after conditioning than during preconditioning (rats: 402.4 ± 61.3 vs. 322.1 ± 45.0 s, 10 mg/kg, n = 9, P = 0.009; mice: 437.8 ± 59.4 vs. 351.3 ± 95.9 s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin [D-Arg2, Lys4] (1-4) amide (5 µM, 1 µl, n = 5) reduced the numbers of small-diameter dorsal root ganglion neurons that showed spontaneous activity (1.1 ± 0.4 vs. 1.5 ± 0.3, P = 0.044) and that were activated by test stimulation (15.5 ± 5.5 vs. 28.2 ± 8.2, P = 0.009) after injury. In neuropathic rats, dermorphin [D-Arg2, Lys4] (1-4) amide (10 mg/kg, n = 8) decreased spontaneous firing rates in wide-dynamic range neurons to 53.2 ± 46.6% of predrug level, and methylnaltrexone (5 mg/kg, n = 9) blocked dermorphin [D-Arg2, Lys4] (1-4) amide-induced place preference and inhibition of wide-dynamic range neurons. Dermorphin [D-Arg2, Lys4] (1-4) amide increased paw withdrawal threshold (17.5 ± 2.2 g) from baseline (3.5 ± 0.7 g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations. CONCLUSIONS: Peripherally acting µ-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance.

Activation of Peripheral µ-opioid Receptors by Dermorphin [D-Arg2, Lys4] (1-4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain.

BACKGROUND: Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects. METHODS: To determine the therapeutic value of peripheral µ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a hydrophilic, peripherally acting µ-opioid receptor agonist, in male and female rats with spinal nerve ligation-induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA's possible mechanisms of action in male rats. RESULTS: DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral µ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber-mediated, but not A-fiber-mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the ß-alanine-induced [Ca] increase (n = 300); capsaicin and ß-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects. CONCLUSIONS: These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.

Mas-Related G Protein-Coupled Receptors Offer Potential New Targets for Pain Therapy.

The founding member of the Mas-related G-protein-coupled receptor (Mrgpr) family was discovered in 1986. Since then, many more members of this receptor family have been identified in multiple species, and their physiologic functions have been investigated widely. Because they are expressed exclusively in small-diameter primary sensory neurons, the roles of Mrgpr proteins in pain and itch have been best studied. This review will focus specifically on the current knowledge of their roles in pathological pain and the potential development of new pharmacotherapies targeted at some Mrgprs for the treatment of chronic pain. We will also discuss the limitations and future scope of this receptor family in pain treatment.

Anomalous Bilateral Communication between the Inferior Alveolar Nerve and the Auriculotemporal Nerve: A Rare Variation.

Branches of the posterior division of the mandibular nerve show various anomalous communications in the infratemporal region. Understanding such communication has relevance in the management of neuropathies and surgical procedures in this region. This study was conducted to explore such communicating branches, anticipating that they might provide information of clinical significance. A total of 15 human cadavers (30 infratemporal regions) were studied to explore such communicating branches in infratemporal region. The branches of the posterior division of the mandibular nerve were carefully dissected, and these branches were studied and analysed for any abnormal course. In one case, a rare type of bilateral communication between the auriculotemporal nerve and the inferior alveolar nerve, forming a loop with no association with any structure, was observed. It is possible that such communicating branches may be associated with delayed regression of the first arch vessels. The clinical implications of these anomalous communications require further detailed study for improved management of neuropathies and surgical procedures.

Betaine Attenuates Chronic Constriction Injury-Induced Neuropathic Pain in Rats by Inhibiting KIF17-Mediated Nociception.

Kinesin superfamily proteins transport a diverse range of cargo, including excitatory receptors to the dendrite and axon of a neuron via retrograde and anterograde fashions along microtubules, causing central sensitization and neuropathic pain. In this study, we have performed in silico molecular dynamics simulation to delineate the dynamic interaction of betaine with KIF17, a kinesin protein, known to be involved in neuropathic pain. The results from the molecular dynamics study suggest that the betaine-KIF17 complex is stabilized through hydrogen bonding, polar interactions, and water bridges. Findings from in vivo studies suggest a significant increase in pain hypersensitivity, oxido-nitrosative stress, and KIF17 overexpression in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of nerve-injured rats, which was significantly attenuated on treatment with betaine. Betaine treatment also restored the increased NR2B expressions and levels of proinflammatory cytokines and neuropeptides in the DRG and spinal cord of nerve-injured rats. Findings from the current study suggest that betaine attenuates neuropathic pain in rats by inhibiting KIF17-NR2B-mediated neuroinflammatory signaling.

Unlocking the potential of TRPV1 based siRNA therapeutics for the treatment of chemotherapy-induced neuropathic pain.

Chemotherapy-induced neuropathic pain (CINP) is among the most common clinical complications associated with the use of anti-cancer drugs. CINP occurs in nearly 68.1% of the cancer patients receiving chemotherapeutic drugs. Most of the clinically available analgesics are ineffective in the case of CINP patients as the pathological mechanisms involved with different chemotherapeutic drugs are distinct from each other. CINP triggers the somatosensory nervous system, increases the neuronal firing and activation of nociceptive mediators including transient receptor protein vanilloid 1 (TRPV1). TRPV1 is widely present in the peripheral nociceptive nerve cells and it has been reported that the higher expression of TRPV1 in DRGs serves a critical role in the potentiation of CINP. The therapeutic glory of TRPV1 is well recognized in clinics which gives a promising insight into the treatment of pain. But the adverse effects associated with some of the antagonists directed the scientists towards RNA interference (RNAi), a tool to silence gene expression. Thus, ongoing research is focused on developing small interfering RNA (siRNA)-based therapeutics targeting TRPV1. In this review, we have discussed the involvement of TRPV1 in the nociceptive signaling associated with CINP and targeting this nociceptor, using siRNA will potentially arm us with effective therapeutic interventions for the clinical management of CINP.

Emerging role of mitochondria in airborne particulate matter-induced immunotoxicity.

The immune system is one of the primary targets of airborne particulate matter. Recent evidence suggests that mitochondria lie at the center of particulate matter-induced immunotoxicity. Particulate matter can directly interact with mitochondrial components (proteins, lipids, and nucleic acids) and impairs the vital mitochondrial processes including redox mechanisms, fusion-fission, autophagy, and metabolic pathways. These disturbances impede different mitochondrial functions including ATP production, which acts as an important platform to regulate immunity and inflammatory responses. Moreover, the mitochondrial DNA released into the cytosol or in the extracellular milieu acts as a danger-associated molecular pattern and triggers the signaling pathways, involving cGAS-STING, TLR9, and NLRP3. In the present review, we discuss the emerging role of mitochondria in airborne particulate matter-induced immunotoxicity and its myriad biological consequences in health and disease.

Kinesin Nanomotors Mediated Trafficking of NMDA-Loaded Cargo as A Novel Target in Chronic Pain.

Chronic pain is among the most prevalent burdensome disorders worldwide. The N-methyl-d-aspartate (NMDA) receptor system plays a critical role in central sensitization, a primary feature of chronic pain. Despite the proven efficacy of exogenous ligands to this receptor system in preclinical studies, evidence for the clinical efficacy of NMDA antagonists for the treatment of chronic pain is weak. Researchers are studying alternate approaches, rather than direct inhibition of the NMDA receptors in pain processing neurons. This indirect approach utilizes the modulation of molecular switches that regulates the synthesis, maturation, and transport of receptors from cellular organelles to the synaptic membrane. Kinesins are nanomotors that anterogradely transport the cargo using microtubule tracks across the neurons. Various members of the kinesin family, including KIF17, KIF11, KIF5b, and KIF21a, regulate the intracellular transport of NMDA receptors. Pharmacological targeting of these ATP-driven nanomotors could be a useful tool for manipulating the NMDAR functioning. It could provide the potential for the development of a novel strategy for the management of chronic pain.

Probing the Manipulated Neurochemical Drive in Alcohol Addiction and Novel Therapeutic Advancements.

Alcohol addiction is one of the highly prevalent neurological disorders and a major threat to public health in the 21st century. Alcohol addiction affects people from all age groups and often leads to other serious comorbidities. The pathophysiology of alcohol addiction involves imbalance between the excitatory and inhibitory neurotransmitters in the brain. These changes occur in various regions of the brain including reward circuit such as the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex. In this review, we have discussed several neurochemical circuitries which get manipulated and maladapted during alcohol addiction. To date there is no effective therapeutic intervention in clinics devoid of side effects that can successfully treat the patients suffering from alcohol addiction. Understanding the neurobiological intricacies of alcohol addiction is critical for the development of novel anti-addiction therapeutics. Apart from this, we have also discussed the recent therapeutic milestones for the management of alcohol addiction including vasopressin receptors, corticotrophin-releasing factor, GABA receptors, glucocorticoid receptors, brain stimulation and mindfulness-oriented recovery enhancement.

Adenosine receptor signalling: Probing the potential pathways for the ministration of neuropathic pain.

Neuropathic pain is a critical burdensome problem due to the complex interplay of several pathological mechanisms and lack of availability of effective therapeutic interventions. The available therapeutic options are associated with a variety of limitations, including severe side effects, and unmet medical needs, warranting further research to identify and validate potential targets. Adenosine receptors system is a widely studied target, which evidently was successful in alleviation of neuropathic pain in several experimental paradigms, and researchers are putting efforts in building its clinical roadmap. The adenosine receptors act by different mechanisms and targeting adenosine receptors for neuropathic pain includes several important pathways such as p38-mitogen-activated protein kinases (MAPK), extracellular signal-regulated kinases (ERK), brain-derived neurotrophic factor (BDNF) signalling, γ-aminobutyric acid (GABA) as well as the ion channel modulations. Various studies have also shown the relevance of targeting adenosine receptors in chemotherapy-induced neuropathic pain and diabetic neuropathy. Several drugs acting on adenosine receptors have undergone clinical trials for management of neuropathic pain, whereas many other drugs are yet to be studied to find a potential anti-nociceptive agent. In this review, we have discussed the roadmap of adenosine receptors as a potential target for the treatment of neuropathic pain.

Activation of µ-δ opioid receptor heteromers inhibits neuropathic pain behavior in rodents.

Several reports support the idea that µ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of µ-δ heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on µ-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-δ heteromer-targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-δ heteromer expression in L5 DRG but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC50: 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, subcutaneously). HEK-293T cell surface-labeled with µ- and δ-ORs internalized both receptors after exposure to CYM51010. By contrast, in cells transfected with µ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats but was markedly attenuated in µ-OR knockout mice. Our studies show that spinal nerve injury may increase µ-δ heterodimerization in uninjured DRG neurons, and that µ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.