Peripheral Effects Research Articles

Mendelian Randomization Analysis Reveals Statins Potentially Increase Amyotrophic Lateral Sclerosis Risk Independent of Peripheral Cholesterol-Lowering Effects.

Observational studies suggest that statins may affect amyotrophic lateral sclerosis (ALS). However, they are limited by confounding and reverse causality biases. Therefore, we aimed to investigate the potential causal associations between statins and ALS using a mendelian randomization (MR) approach. Two-sample MR and drug-target MR were performed. Exposure sources included GWAS summary statistics of statin use, low-density-lipoprotein cholesterol (LDL-C), HMGCR-mediated LDL-C and LDL-C response to statins. Genetic predisposition to statin medication was associated with increased ALS risk (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005). After removing SNPs significantly associated with statin use from the instrumental variables (IVs), LDL-C-related higher ALS risk was absent (before removing: OR = 1.075, 95% CI = 1.013-1.141, p = 0.017; after removing: OR = 1.036, 95% CI = 0.949-1.131, p = 0.432). HMGCR-mediated LDL-C (OR = 1.033, 95% CI = 0.823-1.296, p = 0.779) and blood LDL-C response to statins (OR = 0.998, 95% CI = 0.991-1.005, p = 0.538) had no association with ALS. Here, we show that statins may be a risky exposure that increases ALS risk independent of the lowering effect of LDL-C in peripheral circulation. This provides insights into ALS development and prevention.

Recent Trends in Nano-Particulate Carriers for the Diagnosis and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the presence of aggregated amyloid fibers, neurodegeneration, and loss of memory. Although "Food and Drug Administration" (FDA) approved drugs are available to treat AD, drugs that target AD have limited access to the brain and cause peripheral side effects. These peripheral side effects are the results of exposure of peripheral organs to the drugs. The blood-brain barrier (BBB) is a very sophisticated biological barrier that allows the selective permeation of various molecules or substances. This selective permeation by the BBB is beneficial and protects the brain from unwanted and harmful substances. However, this kind of selective permeation hinders the access of therapeutic molecules to the brain. Thus, a peculiar drug delivery system (nanocarriers) is required. Due to selective permeation of the "blood-brain barrier," nanoparticulate carriers may provide special services to deliver the drug molecules across the BBB. This review article is an attempt to present the role of different nanocarriers in the diagnosis and treatment of Alzheimer's disease. Peer-reviewed and appropriate published articles were collected for the relevant information. Nanoparticles not only traverse the blood-brain barrier but may also play roles in the detection of amyloid β, diagnosis, and drug delivery. Based on published literature, it could be concluded that nano-particulate carriers may traverse the blood-brain barrier via the transcellular pathway, receptor-mediated endocytosis, transcytosis, and may enhance the bioavailability of drugs to the brain. Hence, peripheral side effects could be avoided.

Role of circadian rhythms and melatonin in bladder function in heath and diseases

The circadian system modulates all visceral organ physiological processes including urine storage and voiding. The "master clock" of the circadian system lies within suprachiasmatic nucleus of the hypothalamus while "peripheral clocks" are found in most peripheral tissue and organs, including the urinary bladder. Disruptions of circadian rhythms can cause organ malfunction and disorder or exacerbate pre-existing ones. It has been suggested that nocturia, which develops mostly in the elderly, could be a circadian-related disorder of the bladder. In the bladder, many types of gap junctions and ion channels in the detrusor, urothelium and sensory nerves are likely under strict local peripheral circadian control. The pineal hormone, melatonin, is a circadian rhythm synchroniser capable of controlling a variety of physiological processes in the body. Melatonin predominantly acts via the melatonin 1 and melatonin 2 G-protein coupled receptors expressed in the central nervous system, and many peripheral organs and tissues. Melatonin could be beneficial in the treatment of nocturia and other common bladder disorders. The ameliorating action of melatonin on bladder function is likely due to multiple mechanisms which include central effects on voiding and peripheral effects on the detrusor and bladder afferents. More studies are warranted to determine the precise mechanisms of circadian rhythm coordination of the bladder function and melatonin influences on the bladder in health and diseases.

The Pharmacokinetics of Subcutaneous Methylnaltrexone Bromide in Rhesus Macaques (Macaca mulatta).

Opioids are an integral component of pain management for nonhuman primates. These potent analgesics also adverse gastrointestinal (GI) effects that include constipation, bloating, and delayed gastric emptying. Methylnaltrexone bromide (MNTX) is a selective, peripherally acting μ- and κ-opioid receptor antagonist that can be used to mitigate the GI effects associated with opioid administration. Unlike naltrexone, a similar drug in this class, MNTX possesses an N-methyl-quaternary amine group that prevents it from crossing the blood brain barrier. This blockage allows inhibition of peripheral GI opioid receptors without affecting opioid-mediated analgesia in the central nervous system. We conducted a pharmacokinetic analysis of MNTX in serum and CSF of 6 healthy juvenile male rhesus macaques after subcutaneous administration of a 0.15-mg/kg dose. We hypothesized that the macaques would demonstrate a Tmax of 0.5 h, similar to that of humans, and that no MNTX would be detected in the CSF. This treatment resulted in a peak serum concentration of 114 ± 44 ng/mL at 0.25 ± 0.00 h; peak CSF at concentrations were 0.34 ± 0.07 ng/mL at the Tmax. These data show that subcutaneous administration of MNTX to rhesus macaques may block peripheral adverse effects of opioids without interfering with their central analgesic effects.

Local analgesia of electroacupuncture is mediated by the recruitment of neutrophils and released β-endorphins.

The efficacy of acupuncture in treating pain diseases has been recognized in clinical practice, and its mechanism of action has been a hot topic in academic acupuncture research. Previous basic research on acupuncture analgesia has focused mostly on the nervous system, with few studies addressing the immune system as a potential pathway of acupuncture analgesia. In this study, we investigated the effect of electroacupuncture (EA) on the β-endorphins (β-END) content, END-containing leukocyte type and number, sympathetic neurotransmitter norepinephrine (NE), and chemokine gene expression in inflamed tissues. To induce inflammatory pain, about 200 µL of complete Frester adjuvant (CFA) was injected into the unilateral medial femoral muscle of adult Wistar rats. Electroacupuncture treatment was performed for 3 days beginning on day 4 after CFA injection, with parameters of 2/100 Hz, 2 mA, and 30 minutes per treatment. The weight-bearing experiment and enzyme-linked immunosorbent assay showed that EA treatment significantly relieved spontaneous pain-like behaviors and increased the level of β-END in inflamed tissue. Injection of anti-END antibody in inflamed tissue blocked this analgesic effect. Flow cytometry and immunofluorescence staining revealed that the EA-induced increase in β-END was derived from opioid-containing ICAM-1 + /CD11b + immune cells in inflamed tissue. In addition, EA treatment increased the NE content and expression of β2 adrenergic receptor (ADR-β2) in inflammatory tissues and upregulated Cxcl1 and Cxcl6 gene expression levels. These findings provide new evidence for the peripheral analgesic effect of acupuncture treatment by recruiting β-END-containing ICAM-1 + /CD11b + immune cells and increasing the β-END content at the site of inflammation.

TAAR1 Agonist Ulotaront Improves Glycemic Control and Reduces Body Weight in Rodent Models of Diabetes, Obesity, and Iatrogenic Weight Gain

AbstractIntroductionPreclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is a TAAR1 and 5-HT1A agonist currently in Phase 3 clinical trials for the treatment of schizophrenia. Here we summarize preclinical results assessing the effects of ulotaront on weight and metabolic parameters.MethodsEffects of ulotaront administration were evaluated on oral glucose tolerance (oGTT), gastric emptying, and in rodent models of weight gain (high-fat diet [HFD]-, corticosterone-, and olanzapine-induced).ResultsFollowing 15-day oral administration of ulotaront, rats on HFD showed dose-dependent reduction in body weight, food intake, and liver triglyceride content compared to controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in rats switched to ulotaront (vs. vehicle). Consistent with weight-lowering effects in rats, chronic ulotaront treatment normalized corticosterone-induced weight gain in mice. Assessment of oGTT showed a dose-dependent reduction of glucose excursion in response to acute ulotaront administration in naive and diabetic db/db mice. Ulotaront administration also delayed gastric emptying in mice—a likely mechanism driving reductions in glucose excursions during the oGTT. Whole-brain c-fos imaging of ulotaront-treated mice revealed increased neuronal activity in several brain regions associated with regulation of food intake and metabolic signals.ConclusionsThe data indicate that ulotaront not only lacks metabolic liabilities typically associated with antipsychotics but can reduce body weight and improve glucose tolerance in rodent models. The underlying mechanisms may include TAAR1-mediated peripheral effects on glucose homeostasis and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance. The beneficial metabolic effects of ulotaront may suggest a substantially improved risk-benefit profile compared to established antipsychotics.FundingSunovion Pharmaceuticals Inc. and Otsuka Pharmaceutical Development & Commercialization, Inc.

Antioxidant activity, analgesic activity, and phytochemical analysis of Ammi majus (L.) extracts

Ammi majus (L.) is commonly used to cure many diseases in Moroccan folk medicine, especially vitiligo. This research tries to evaluate the phytochemical constituents of two aqueous extracts (E1; Maceration; 48 h) and (E2: Infusion; 1h) and three organic fractions (F1: Cyclohexane), (F2: Ethyl acetate (EtOAc)) and (F3: Ethanolic (EtOH)) of A. majus (L.) seeds, as well as to study the antioxidant and analgesic activity of the species. Phytochemical analysis, antioxidant activity (DPPH, FRAP, ABTS, and TAC tests), and analgesic activity (writhing and tail immersion were induced by Acetic acid tests) were analyzed according to the literature. A quantitative phytochemical study indicate that the E1 had the highest content of total polyphenols (26.95 ± 0.53 mg GAE/g extract) and flavonoids (37.92 ± 0.46 mg QE/g extract), while F3 showed a promising flavonol content (24.26±0.08 mg QE/g extract). Tannins were found to be high in F1 (59.27 ± 0.16 mg CE/g extract) and F2 (57.65 ± 1.18 mg CE/g extract). Antioxidant results reveals that DPPH (IC50 = 179.68 ± 0.47 μg/mL) and FRAP (EC50 = 367.03 ± 0.12 μg/mL) show to E1 a high antioxidant activity. Regarding the analgesic activity of the different studied extracts, it was found that E1 has a high peripheral analgesic effect with 62.32 % and a high central analgesic potential throughout the experimentation at 500 mg/kg. Our studies demonstrated for the first time that A. majus seeds extracts have high antioxidant and analgesic activities through different analysis techniques.

Neuronal loss of TRPM8 leads to obesity and glucose intolerance in male mice

ObjectiveMice with global deletion of the transient receptor potential channel melastatin family member 8 (TRPM8) are obese, and treatment of diet-induced obese (DIO) mice with TRPM8 agonists decrease body weight. Whether TRPM8 signaling regulates energy metabolism via central or peripheral effects is unknow. Here we assessed the metabolic phenotype of mice with either Nestin Cre-mediated neuronal loss of TRPM8, or with deletion of TRPM8 in Advillin Cre positive sensory neurons of the peripheral nervous system (PNS). MethodsNestin Cre- and Advillin Cre-Trpm8 knock-out (KO) mice were metabolically phenotyped under chronic exposure to either chow or high-fat diet (HFD), followed by assessment of energy and glucose metabolism. ResultsAt room temperature, chow-fed neuronal Trpm8 KO are obese and show decreased energy expenditure when acutely treated with the TRPM8 selective agonist icilin. But body weight of neuronal Trpm8 KO mice is indistinguishable from wildtype controls at thermoneutrality, or when mice are chronically exposed to HFD-feeding. In contrast to previous studies, we show that the TRPM8 agonist icilin has no direct effect on brown adipocytes, but that icilin stimulates energy expenditure, at least in part, via neuronal TRPM8 signaling. We further show that lack of TRPM8 in sensory neurons of the PNS does not lead to a metabolically relevant phenotype. ConclusionsOur data indicate that obesity in TRPM8-deficient mice is centrally mediated and likely originates from alterations in energy expenditure and/or thermal conductance, but does not depend on TRPM8 signaling in brown adipocytes or sensory neurons of the PVN.

Acute toxicity, analgesic and anti-inflammatory effects of soursop leaf ethanol extract (Annona muricata l.) in vivo

This study tested the peripheral analgesic effect of leaf extract by injecting 1% acetic acid on the peritoneum of white mice; tested the central analgesic effect by dipping the mice's tail in hot water (52 ± 0.5) °C; tested the acute anti-inflammatory effect by injecting carrageenan into the paws of mice causing edema; tested the chronic an- ti-inflammatory effect by injecting Freund's complete adjuvant (FCA) into the paws of mice causing edema. The control drugs used in the trials were diclofenac and codeine. Result: LD50 of the Annona muricata leaf ethanol extract was 0.705 mg/kg; The study showed that at all 3 doses, 35 mg/kg, 70 mg/kg and 140 mg/kg Annona muricata leaf extract had anti-inflammatory effects on acute and chronic inflammation; central and peripheral analgesic effects on mice.

Alpha Synuclein: Neurodegeneration and Inflammation.

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in the pathogenesis of Parkinson's disease and related disorders, synucleinopathies, but also in several other neurodegenerative disorders with a more elusive role. This review analyzes the activities of α-Syn, in different conformational states, monomeric, oligomeric and fibrils, in relation to neuronal dysfunction. The neuronal damage induced by α-Syn in various conformers will be analyzed in relation to its capacity to spread the intracellular aggregation seeds with a prion-like mechanism. In view of the prominent role of inflammation in virtually all neurodegenerative disorders, the activity of α-Syn will also be illustrated considering its influence on glial reactivity. We and others have described the interaction between general inflammation and cerebral dysfunctional activity of α-Syn. Differences in microglia and astrocyte activation have also been observed when in vivo the presence of α-Syn oligomers has been combined with a lasting peripheral inflammatory effect. The reactivity of microglia was amplified, while astrocytes were damaged by the double stimulus, opening new perspectives for the control of inflammation in synucleinopathies. Starting from our studies in experimental models, we extended the perspective to find useful pointers to orient future research and potential therapeutic strategies in neurodegenerative disorders.

The role of L-arginine/NO/cGMP/KATP channel pathway in the local antinociceptive effect of berberine in the rat formalin test.

Berberine is an isoquinoline alkaloid naturally produced by several types of plants. Berberine has extensive pharmacological effects, such as anti-diabetic, anti-inflammatory, and antioxidant effects. In the current study, we assess the antinociceptive effects of berberine and its association with the l-arginine (l-Arg)/NO/cGMP/KATP channel pathway via intraplantar administration in rats. To examine the antinociceptive properties of berberine, the formalin test was conducted. The number of rat paw flinches was counted for an h. l-Arg (precursor of nitric oxide, 3-30 μg/paw), l-NAME (NO synthase inhibitor, 10 and 100 μg/paw), methylene blue (guanylyl cyclase inhibitor, 100 and 200 μg/paw), and glibenclamide (ATP-sensitive potassium channel blocker, 10 and 30 μg/paw) were locally injected, respectively, into the right hind paws of rats as a pre-treatment before berberine injection to understand how the l-Arg/NO/cGMP/KATP pathway plays a role in the antinociceptive effect of berberine. The ipsilateral injection of berberine into the right paw (0.1-100 μg/paw) showed a dose-dependent antinociceptive effect in both the first and second phases of the formalin test, almost similar to morphine (25 μg/paw). Intraplantar injection of l-Arg (30 µg/paw) increased the antinociceptive effect of berberine in the second phase. In addition, injection of l-NAME, methylene blue, and glibenclamide caused a reduction in the antinociceptive effect of berberine throughout the second phase in a dose-dependent manner. However, the antinociceptive effects of berberine in the first phase of the rat formalin test were not affected by this pathway. As a novel local antinociceptive agent, berberine can exert a peripheral antinociceptive effect via the l-Arg/NO/cGMP/KATP channel pathway.

Effect of Flavoring with Rosemary, Lemon and Orange on the Quality, Composition and Biological Properties of Olive Oil: Comparative Study of Extraction Processes

The goal of this work was to investigate the impact of the flavoring of some aromatic plants/spices, including rosemary (R), lemon (L) and orange (O) at the concentration of 5% and 35% (w/w) added by 2 methods (conventional maceration and direct flavoring), on quality attributes, chemical changes and oxidative stability of extra virgin olive oil (EVOO). Six flavored oils were obtained (EVOO + O, O + O, EVOO + R, O + R, EVOO + L and O + L). The physicochemical parameters (water content, refractive index, acidity and peroxide value, extinction coefficient, fatty acids, volatile aroma profiles, Rancimat test, phenols and pigments composition) of the flavored oils were investigated. Based on the results obtained, it was observed that flavoring with a conventional process provided increased oxidative stability to the flavored oils, especially with rosemary (19.38 ± 0.26 h), compared to that of unflavored oil. The volatile profiles of the different flavored oils revealed the presence of 34 compounds with the dominance of Limonene. The fatty acid composition showed an abundance of mono-unsaturated fatty acids followed by poly-unsaturated ones. Moreover, a high antioxidant activity, a significant peripheral analgesic effect (77.7% of writhing inhibition) and an interesting gastroprotective action (96.59% of ulcer inhibition) have been observed for the rosemary-flavored oil. Indeed, the flavored olive oils of this study could be used as new functional foods, leading to new customers and further markets.

A comparison between different variants of the spatial Stroop task: The influence of analytic flexibility on Stroop effect estimates and reliability.

The spatial Stroop task measures the ability to resolve interference between relevant and irrelevant spatial information. We recently proposed a four-choice spatial Stroop task that ensures methodological advantages over the original color-word verbal Stroop task, requiring participants to indicate the direction of an arrow while ignoring its position in one of the screen corners. However, its peripheral spatial arrangement might represent a methodological weakness and could introduce experimental confounds. Thus, aiming at improving our "Peripheral" spatial Stroop, we designed and made available five novel spatial Stroop tasks (Perifoveal, Navon, Figure-Ground, Flanker, and Saliency), wherein the stimuli appeared at the center of the screen. In a within-subjects online study, we compared the six versions to identify which task produced the largest but also the most reliable and robust Stroop effect. Indeed, although internal reliability is frequently overlooked, its estimate is fundamental, also in light of the recently proposed reliability paradox. Data analyses were performed using both the classical general linear model analytical approach and two multilevel modelling approaches (linear mixed models and random coefficient analysis), which specifically served for more accurately estimating the Stroop effect by explaining intra-subject, trial-by-trial variability. We then assessed our results based on their robustness to such analytic flexibility. Overall, our results indicate that the Perifoveal spatial Stroop is the best alternative task for its statistical properties and methodological advantages. Interestingly, our results also indicate that the Peripheral and Perifoveal Stroop effects were not only the largest, but also those with highest and most robust internal reliability.

RIPK necrotic cell death pathway in both donor photoreceptor and host immune cells synergize to affect photoreceptor graft survival.

Photoreceptor transplant has been put forward as a repair strategy to tackle degenerated retinas. Nonetheless, cell death and immune rejection seriously limit the success of this strategy, with only a small fraction of transplanted cells surviving. Improving the survival of transplanted cells is of critical importance. Recent evidence has identified receptor-interacting protein kinase 3 (RIPK3) as a molecular trigger controlling necroptotic cell death and inflammation. However, its role in photoreceptor transplantation and regenerative medicine has not been studied. We hypothesized that modulation of RIPK3 to address both cell death and immunity could have advantageous effects on photoreceptor survival. In a model of inherited retinal degeneration, deletion of RIPK3 in donor photoreceptor precursors significantly increases the survival of transplanted cells. Simultaneous RIPK3 deletion in donor photoreceptors and recipients maximizes graft survival. Lastly, to discern the role of RIPK3 in the host immune response, bone marrow transplant experiments demonstrated that peripheral immune cell RIPK3 deficiency is protective for both donor and host photoreceptor survival. Interestingly, this finding is independent of photoreceptor transplantation, as the peripheral protective effect is also observed in an additional retinal detachment photoreceptor degeneration model. Altogether, these results indicate that immunomodulatory and neuroprotective strategies targeting the RIPK3 pathway can aid regenerative therapies of photoreceptor transplantation.

Next-generation antipsychotics- Trends and perspectives beyond dopaminergic and glutamatergic agents

IntroductionThree generations of antipsychotics, all of which are based on the dopaminergic hypothesis of schizophrenia, are available for clinical use. Still, more than 66% of the patients diagnosed with schizophrenia spectrum disorders (SSD) could not achieve remission. Also, the glutamatergic hypothesis of schizophrenia is supported by translational models of this disease, even if the antipsychotics derived from this conceptual framework are not yet available on the market. However, the need for new pathogenesis models for schizophrenia and new generations of antipsychotics is acute, therefore, an exploration of the antipsychotics in the pipeline could be helpful in understanding the current stage of research in schizophrenia.ObjectivesTo assess the evidence supporting the potential benefits of new antipsychotics in the pipeline.MethodsA literature review was performed through the main electronic databases PubMed, Cochrane, Clarivate/Web Of Science, and EMBASE) and clinical trials repositories (US National Library of Medicine and World Health Organization Clinical Trials Registry Platform) using the search paradigm “antipsychotics” AND “schizophrenia” AND “non-dopaminergic” AND “non-glutamatergic”. All papers published between January 2010 and September 2022 were included.ResultsXanomeline/trospium (xanomeline is a muscarinic M1/M4 receptor agonist at the central nervous system, while trospium limits its peripheral effects) was efficient for schizophrenia in one phase III clinical trial. Pimavanserin (a selective 5HT2A inverse agonist and antagonist) was efficient in improving negative symptoms of schizophrenia in a phase II trial. Roluperidone (a 5HT2A and σ2 receptor antagonist) has been associated with favorable results in phase III clinical trials, mainly on negative symptoms of schizophrenia. SEP-363856 is a TAAR-1 agonist and 5HT1A agonist, currently explored in phase III clinical trials for schizophrenia. MK-8189 is a phosphodiesterase 10A inhibitor, investigated in phase III clinical trials for schizophrenia.ConclusionsBased on the retrieved data in the literature, multiple mechanisms, other than glutamatergic and dopaminergic pathways, are currently being investigated, and many of the antipsychotics based on these mechanisms are in the advanced stage of research. This is important not only for the clinical need to find more efficient and tolerable drugs for patients with schizophrenia but also because they may shed new light on the pathogenesis of this disease.Disclosure of InterestNone Declared

Repetitive Noxious Stimulation with Formalin, Capsaicin, and Freund’s Adjuvant Facilitates Monitoring of the Peripheral and Central Pain Effects

Repetitive Noxious Stimulation with Formalin, Capsaicin, and Freund’s Adjuvant Facilitates Monitoring of the Peripheral and Central Pain Effects

The Inhibitory Effect of Adenylic Acid on the Bitterness of the Antibacterial Combination Drug Trimethoprim/Sulfamethoxazole.

The purpose of the present study was to evaluate bitterness suppression effect of adenylic acid (AMP) as a nucleotide-derived nutrient enhancer on a bitter commercial drug. In the present study, we evaluated peripheral bitterness inhibition effect of AMP on the trimethoprim (TMP) and sulfamethoxazole (SMZ) combination formulation based on taste sensor. The taste sensor values of TMP solutions with different concentrations show large sensor output in correlation with the concentration of TMP, whereas no sensor output in shown for the SMZ solutions. Therefore, the bitterness of this combination formulation is mainly due to TMP. We evaluated the TMP bitterness inhibitory effects of AMP, sodium salt of AMP (AMP Na; sodium adenylate), sodium salt of GMP (GMP Na; sodium guanylate), and sodium salt of inosine monophosphate (IMP Na; sodium inosinate), and found that only AMP displayed very effective bitterness inhibition. MarvinSketch analysis revealed that potential electrostatic interaction between cationized TMP and anionized forms (II and III) of AMP may cause bitterness suppression. 1H-NMR study suggested an interaction of TMP and AMP molecules based on chemical shift perturbations and an interaction between the phosphate group of AMP and amino group of TMP. Lastly, conventional elution analysis simulating oral cavity capacity for up to one minute were performed using commercial TMP/SMZ combination granules. The sensor output gradually increased up to 60 s. The addition of AMP solution to the eluted sample at 60 s significantly decreased the bitterness sensor output of the eluted sample.

Modulation of social behavior by distinct vasopressin sources.

The neuropeptide arginine-vasopressin (AVP) is well known for its peripheral effects on blood pressure and antidiuresis. However, AVP also modulates various social and anxiety-related behaviors by its actions in the brain, often sex-specifically, with effects typically being stronger in males than in females. AVP in the nervous system originates from several distinct sources which are, in turn, regulated by different inputs and regulatory factors. Based on both direct and indirect evidence, we can begin to define the specific role of AVP cell populations in social behavior, such as, social recognition, affiliation, pair bonding, parental behavior, mate competition, aggression, and social stress. Sex differences in function may be apparent in both sexually-dimorphic structures as well as ones without prominent structural differences within the hypothalamus. The understanding of how AVP systems are organized and function may ultimately lead to better therapeutic interventions for psychiatric disorders characterized by social deficits.

Probiotic Formulation VSL#3 Interacts with Mesenchymal Stromal Cells To Protect Dopaminergic Neurons via Centrally and Peripherally Suppressing NOD-Like Receptor Protein 3 Inflammasome-Mediated Inflammation in Parkinson's Disease Mice.

Systemic immunomodulation is increasingly recognized among the beneficial effects of mesenchymal stromal cells (MSCs) in treatment of Parkinson's disease (PD), while the underlying mechanism is not fully understood. With the growing popularity of using probiotics as an adjuvant approach in PD treatment, concerns about the added effects of probiotics have been raised. In addition to the molecular mechanism mediating the neuroprotective effects of MSCs, the combined effects of a probiotic formulation, VSL#3, and MSC infusion were also evaluated in PD mice. The animals were weekly treated with human MSCs (hMSCs) via the tail vein, VSL#3 via the gastrointestinal tract, or their combination six times. hMSCs, VSL#3 alone, and their combination markedly ameliorated the decreased striatal dopamine content, loss of dopaminergic neurons in the substantia nigra, increased levels of proinflammatory cytokines in serum, as well as tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) mRNAs in striatum and peripheral tissues induced by MPTP. Furthermore, hMSCs, VSL#3, and their combination notably downregulated mRNA expression of NOD-like receptor protein 3 (NLRP3) and caspase-1 in brain and peripheral tissues of PD mice. These results suggest that hMSCs, VSL#3, and their combination prevent neurodegenerative changes in PD mice via anti-inflammatory activities in both the central and peripheral systems, possibly through suppressing the NLRP3 inflammasome. Moreover, two-way analysis of variance (ANOVA) indicated that VSL#3 interacts with hMSCs to attenuate neurodegeneration and inhibit NLRP3 inflammasome-mediated inflammation without altering the effects of hMSCs. Major findings of our study support the usage of probiotic formulation VSL#3 as an adjuvant therapy to hMSC infusion in PD treatment. IMPORTANCE This study provides evidence for the neuroprotective activities of human umbilical cord MSCs from the aspect of anti-inflammation actions. hMSCs inhibit the NLRP3 inflammasome and MPTP-induced inflammation in both brain and periphery to relieve the degenerative changes in dopaminergic neurons in PD mice. Furthermore, as an additional therapeutic agent, probiotic formulation VSL#3 interacts with hMSCs in suppressing the NLRP3 inflammasome as well as the central and peripheral anti-inflammatory effects to exert neuroprotective actions in PD mice without altering the actions of hMSCs, suggesting the potential of VSL#3 as an adjuvant therapy in PD treatment. The findings of the present study give a further understanding of the anti-inflammatory activity and the molecular mechanism for the beneficial effects of MSCs as well as the potential application of probiotic formulation as an adjuvant approach to MSC therapy in PD treatment.

Neuromodulatory functions exerted by oxytocin on different populations of hippocampal neurons in rodents.

Oxytocin (OT) is a neuropeptide widely known for its peripheral hormonal effects (i.e., parturition and lactation) and central neuromodulatory functions, related especially to social behavior and social, spatial, and episodic memory. The hippocampus is a key structure for these functions, it is innervated by oxytocinergic fibers, and contains OT receptors (OTRs). The hippocampal OTR distribution is not homogeneous among its subregions and types of neuronal cells, reflecting the specificity of oxytocin's modulatory action. In this review, we describe the most recent discoveries in OT/OTR signaling in the hippocampus, focusing primarily on the electrophysiological oxytocinergic modulation of the OTR-expressing hippocampal neurons. We then look at the effect this modulation has on the balance of excitation/inhibition and synaptic plasticity in each hippocampal subregion. Additionally, we review OTR downstream signaling, which underlies the OT effects observed in different types of hippocampal neuron. Overall, this review comprehensively summarizes the advancements in unraveling the neuromodulatory functions exerted by OT on specific hippocampal networks.