Looking for a Beam of Light to Heal Chronic Pain.

Chronic pain (CP) is a leading cause of disability and a potential factor that affects biological processes, family relationships, and self-esteem of patients. However, the need for treatment of CP is presently unmet. Current methods of pain management involve the use of drugs, but there are different degrees of concerning side effects. At present, the potential mechanisms underlying CP are not completely clear. As research progresses and novel therapeutic approaches are developed, the shortcomings of current pain treatment methods may be overcome. In this review, we discuss the retinal photoreceptors and brain regions associated with photoanalgesia, as well as the targets involved in photoanalgesia, shedding light on its potential underlying mechanisms. Our aim is to provide a foundation to understand the mechanisms underlying CP and develop light as a novel analgesic treatment has its biological regulation principle for CP. This approach may provide an opportunity to drive the field towards future translational, clinical studies and support pain drug development.

Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development.

Premenstrual dysphoric disorder (PMDD) can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones. Its core symptoms (emotional instability, irritability, depression, and anxiety) are related to the increase of stress sensitivity due to the fluctuation of hormone level in luteal phase of the menstrual cycle. In this review, we describe the emotional regulatory effect of allopregnanolone (ALLO), and summarize the relationship between ALLO and γ-aminobutyric acid A (GABAA) receptor subunits based on rodent experiments and clinical observations. A rapid decrease in ALLO reduces the sensitivity of GABAA receptor, and reduces the chloride influx, hindered the inhibitory effect of GABAergic neurons on pyramidal neurons, and then increased the excitability of pyramidal neurons, resulting in PMDD-like behavior. Finally, we discuss in depth the treatment of PMDD with targeted GABAA receptors, hoping to find a precise target for drug development and subsequent clinical application. In conclusion, PMDD pathophysiology is rooted in GABAA receptor sensitivity changes caused by rapid changes in ALLO levels. Targeting GABAA receptors may alleviate the occurrence of PMDD.

Curcumin (CUMINUP60®) mitigates exercise fatigue through regulating PI3K/Akt/AMPK/mTOR pathway in mice.

Curcumin is a chemical constituent extracted from Curcuma longa L. Several clinical and preclinical studies have demonstrated that it can mitigate exercise fatigue, but the exact mechanism is still unknown. Therefore, we applied a mouse model of exercise fatigue to investigate the possible molecular mechanisms of curcumin's anti-fatigue effect. Depending on body mass, Kunming mice were randomly divided into control, caffeine (positive drug), and curcumin groups, and were given 28 days intragastric administration. Both the caffeine group and curcumin group showed significant improvement in exercise fatigue compared to the control group, as evidenced by the increase in time to exhaustion, as well as the higher quadriceps coefficient, muscle glycogen (MG) content, and increase in the expression of Akt, AMPK, PI3K, and mTOR proteins. While the curcumin group also significantly improved the exercise fatigue of the mice, demonstrating a lower AMP/ATP ratio and lactic acid (LA) content, and increased glycogen synthase (GS), and myonectin content compared to the caffeine group. Therefore, in the present study, we found that curcumin can exert a similar anti-fatigue effect to caffeine and may act by regulating energy metabolism through modulating the expression of the proteins in the PI3K/Akt/AMPK/mTOR pathway.

Oxytocin and serotonin in the modulation of neural function: Neurobiological underpinnings of autism-related behavior.

Autism spectrum disorders (ASD) is a group of generalized neurodevelopmental disorders. Its main clinical features are social communication disorder and repetitive stereotyped behavioral interest. The abnormal structure and function of brain network is the basis of social dysfunction and stereotyped performance in patients with autism spectrum disorder. The number of patients diagnosed with ASD has increased year by year, but there is a lack of effective intervention and treatment. Oxytocin has been revealed to effectively improve social cognitive function and significantly improve the social information processing ability, empathy ability and social communication ability of ASD patients. The change of serotonin level also been reported affecting the development of brain and causes ASD-like behavioral abnormalities, such as anxiety, depression like behavior, stereotyped behavior. Present review will focus on the research progress of serotonin and oxytocin in the pathogenesis, brain circuit changes and treatment of autism. Revealing the regulatory effect and neural mechanism of serotonin and oxytocin on patients with ASD is not only conducive to a deeper comprehension of the pathogenesis of ASD, but also has vital clinical significance.

A forced swim-based rat model of premenstrual depression: effects of hormonal changes and drug intervention.

Premenstrual dysphoric disorder (PMDD), a form of premenstrual syndrome (PMS), is a severe health disturbance that affects a patient's emotions; it is caused by periodic psychological symptoms, and its pathogenesis remains unclear. As depression-like symptoms are found in a majority of clinical cases, a reliable animal model of premenstrual depression is indispensable to understand the pathogenesis. Herein, we describe a novel rat model of premenstrual depression, based on the forced swimming test, with a regular estrous cycle. The results showed that in the estrous cycle, the depression-like behavior of rats occurred in the non-receptive phase and disappeared in the receptive phase. Following ovariectomy, the depression-like symptoms disappeared and returned after a hormone priming regimen. Moreover, fluoxetine, an anti-depressant, could reverse the behavioral symptoms in these model rats with normal estrous cycle. Further, the model rats showed significant changes in the serum levels of estrogen and progesterone, hippocampal levels of allopregnanolone, 5-hydroxytryptamine, norepinephrine, and γ-aminobutyric acid (GABA), and in the expression of GABAA receptor 4α subunit, all of which were reversed to physiological levels by fluoxetine. Overall, we established a reliable and standardized rat model of premenstrual depression, which may facilitate the elucidation of PMS/PMDD pathogenesis and development of related therapies.

Paeonol at Certain Doses Alleviates Aggressive and Anxiety-Like Behaviours in Two Premenstrual Dysphoric Disorder Rat Models.

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS), a common mental health disturbance associated with several periodic psychological symptoms in women. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for PMS/PMDD patients; however, side effects are inevitable, especially in long-term treatment. In previous studies, the natural compound paeonol in Moutan Cortex was found to play effective roles in central nervous system disorders with its anti-inflammatory, anti-oxidant, and neuroprotective effects. Consequently, we assume that paeonol might produce positive effects in the treatment of PMS/PMDD. In this study, the open-field test (OFT) and elevated plus maze (EPM) and light dark box (LDB) tests were performed in mice to determine the optimal dose of paeonol for treating anxiety. Then, paeonol was used to treat the progesterone withdrawal (PWD) and resident intruder paradigm (RIP) rat models of PMDD. Using these two reliable models, the OFT and EPM, LDB, and composite aggressive tests were performed to evaluate the effect of the drug on behavioural symptoms of PMDD. From the dosage screening results, the optimal anti-anxiety dose of paeonol was identified as 17.5 mg/kg/d for 7 days. With regard to the effect of paeonol on PMDD rat models, a significantly improvement was found in the behavioural symptoms, but the effective dose varied in different models. For the PWD model rats, treatment with 6.05 mg/kg paeonol could significantly improve anxiety and irritability, while that with 24.23 mg/kg paeonol resulted in anxiety-like effects in behavioural tests. In RIP model rats, treatment with 12.11 mg/kg paeonol demonstrated excellent effects in improving anxiety, particularly irritable emotional behaviour. In conclusion, our study indicates that paeonol is a potential therapeutic compound for PMS/PMDD; it is a drug option that helps establish dosage guidance for treatment of this condition.

Social defeat stress before pregnancy induces depressive-like behaviours and cognitive deficits in adult male offspring: correlation with neurobiological changes.

BACKGROUND: Epidemiological surveys and studies with animal models have established a relationship between maternal stress and affective disorders in their offspring. However, whether maternal depression before pregnancy influences behaviour and related neurobiological mechanisms in the offspring has not been studied. RESULTS: A social defeat stress (SDS) maternal rat model was established using the resident-intruder paradigm with female specific pathogen-free Wistar rats and evaluated with behavioural tests. SDS maternal rats showed a significant reduction in sucrose preference and locomotor and exploratory activities after 4 weeks of stress. In the third week of the experiment, a reduction in body weight gain was observed in SDS animals. Sucrose preference, open field, the elevated-plus maze, light-dark box, object recognition, the Morris water maze, and forced swimming tests were performed using the 2-month-old male offspring of the female SDS rats. Offspring subjected to pre-gestational SDS displayed enhanced anxiety-like behaviours, reduced exploratory behaviours, reduced sucrose preference, and atypical despair behaviours. With regard to cognition, the offspring showed significant impairments in the retention phase of the object recognition test, but no effect was observed in the acquisition phase. These animals also showed impairments in recognition memory, as the discrimination index in the Morris water maze test in this group was significantly lower for both 1 h and 24 h memory retention compared to controls. Corticosterone, adrenocorticotropic hormone, and monoamine neurotransmitters levels were determined using enzyme immunoassays or radioimmunoassays in plasma, hypothalamus, left hippocampus, and left prefrontal cortex samples from the offspring of the SDS rats. These markers of hypothalamic-pituitary-adrenal axis responsiveness and the monoaminergic system were significantly altered in pre-gestationally stressed offspring. Brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element binding protein (CREB), phosphorylated CREB (pCREB), and serotonin transporter (SERT) protein levels were evaluated using western blotting with right hippocampus and right prefrontal cortex samples. Expression levels of BDNF, pCREB, and SERT in the offspring were also altered in the hippocampus and in the prefrontal cortex; however, there was no effect on CREB. CONCLUSION: We conclude that SDS before pregnancy might induce depressive-like behaviours, cognitive deficits, and neurobiological alterations in the offspring.

Impact of anger emotional stress before pregnancy on adult male offspring.

Previous studies have reported that maternal chronic stress or depression is linked to an increased risk of affective disorders in progeny. However, the impact of maternal chronic stress before pregnancy on the progeny of animal models is unknown. We investigated the behaviors and the neurobiology of 60-day-old male offspring of female rats subjected to 21 days of resident-intruder stress before pregnancy. An anger stressed parental rat model was established using the resident-intruder paradigm and it was evaluated using behavioral tests. Anger stressed maternal rats showed a significant increase in locomotion and aggression but a reduction in sucrose preference. Offspring subjected to pre-gestational anger stress displayed enhanced aggressive behaviors, reduced anxiety, and sucrose preference. Further, offspring subjected to pre-gestational stress showed significant impairments in the recognition index (RI) on the object recognition test and the number of platform crossings in the Morris water maze test. The monoaminergic system was significantly altered in pre-gestationally stressed offspring, and the expression of phosphorylated cyclic adenosine monophosphate response element binding protein (P-CREB), brain-derived neurotrophic factor (BDNF), and serotonin transporter (SERT) levels in pre-gestational stressed offspring were altered in some brain regions. Fluoxetine was used to treat pre-gestational stressed maternal rats and it significantly reduced the changes caused by stress, as evidenced by both behaviors and neural biochemical indexes in the offspring in some but not all cases. These findings suggest that anger stress before pregnancy could induce aggressive behaviors, cognitive deficits, and neurobiological alterations in offspring.

[Study on estrogen receptors alpha and beta in the hippocampus of premenstrual syndrome model rats of gan-qi depression syndrome].

OBJECTIVE: To study the distribution pattern, the protein expressions, and changes of functional activities of estrogen receptor (ER) alpha and beta in the hippocampus of premenstrual syndrome (PMS) rats of Gan-qi depression syndrome (GDS), and to find out corresponding effect targets of Jingqianshu Granule (JG), thus providing clues for exploring the pathogenesis of PMS of GDS and the mechanisms of JG. METHODS: SD rats were randomly divided into three groups, i. e., the normal group, the model group, and the medication group, 7 in each. Resident intruder stress was used to establish the model in the model group and the medication group. JG was given to rats in the medication group at the dose of 10 mL/kg by gastrogavage while modeling. Equal volume of sterilized water was given to rats in the model group and the normal group, once daily, for 5 successive days. Then the location, protein levels, and ligand-binding capacities of ERalpha and ERbeta in the hippocampus of rats in three groups were detected using immunohistochemical assay, Western blot, and dextran-active carbon binding assay. RESULTS: There was no difference in the distribution pattern of ERalpha and ERbeta in the hippocampus of the three groups. In aspects of protein levels and estrogen-binding capacities of ERalpha and ERbeta in the hippocampus, CA1 and CA3 regions, they increased more obviously in the model group than in the normal group (P < 0.05), while they decreased more significantly in the medication group than in the model group (P < 0.05). CONCLUSION: Higher estrogen levels and enhanced expressions and activities of ERalpha and ERbeta in the hippocampus might be important mechanisms for PMS of GDS, which might also be the effect targets for JG.