Attenuation of alcohol withdrawal syndrome and blood cortisol level with forced exercise in comparison with diazepam

Relieving withdrawal and post-abstinence syndrome of alcoholism is one of the major strategies in the treatment of alcohol addicted patients. Diazepam, chlordiazepoxide, and topiramate are the approved medications that were used for this object. To assess the role of non-pharmacologic therapy in the management of alcohol withdrawal syndrome, we analyzed effects of forced exercise by treadmill on alcohol dependent mice as an animal model. A total of 60 adult male mice were divided into 5 groups, from which 4 groups became dependent to alcohol (2 g/kg/day) for 15 days. From day 16, treatment groups were treated by diazepam (0.5mg/kg), forced exercise, and diazepam (0.5 mg/kg) concurrent with forced exercise for two weeks; And the positive control group received same dose of alcohol (2 g/kg/day) for two weeks. The negative control group received normal saline for four weeks. Finally, on day 31, all animals were observed for withdrawal signs, and Alcohol Total Withdrawal Score (ATWS) was determined. Blood cortisol levels were measured in non-fasting situations as well. Present findings showed that ATWS significantly decrease in all treatment groups in comparison with positive control group (P<0.05 for groups received diazepam and treated by forced exercise and P<0.001 for group under treatment diazepam + forced exercise). Moreover, blood cortisol level significantly decreased in all treatment groups (P<0.001). This study suggested that forced exercise and physical activity can be useful as adjunct therapy in alcoholism and can ameliorate side effects and stress situation of withdrawal syndrome periods. © 2015 Tehran University of Medical Sciences. All rights reserved

Attenuation of morphine physical dependence and blood levels of cortisol by central and systemic administration of ramelteon in rat

Background: Chronic administration of morphine cause physical dependence but the exact mechanism of this phenomenon remains unclear. The aim of this study is the assessment of systemic and intracerebroventricular (icv) administration of ramelteon (a melatonin receptor agonist) on morphine physical dependence. Methods: 88 adult male rats were divided into 2 major groups, namely �systematic� and �central� administration of ramelteon. In the first category, systemic administration of ramelteon at various dosages (10, 20, and 40 mg/kg) was assessed on dependent animals and withdrawal signs were compared with positive (received morphine and saline as systemic administration), negative control (saline) and group under treatment by ramelteon (40 mg/kg) groups. In the second category, central administration of ramelteon at various dosages (25, 50, or 100 μg,) was assessed on dependent animals and withdrawal signs were compared with the positive control (received morphine and saline as icv) and negative control (saline) groups, and the group under treatment by ramelteon (50 μg/5 μl/rat). On the test day, all animals received naloxone (3 mg/kg) and were observed for withdrawal signs. Total withdrawal score (TWS) was also determined. Finally, to evaluate the stress level of dependent rats, blood cortisols were measured. Results: Central administration of ramelteon in all doses and systemic administration in high doses attenuate withdrawal syndrome in comparison with the dependent positive control group (P<0.05). Both central and systemic administrations of ramelteon can attenuate the blood cortisol level in comparison with the dependent positive control group (P<0.05). Conclusion: In conclusion, we found that central administration of ramelteon attenuated morphine withdrawal symptoms and cortisol level as a stress marker. © 2015 Shiraz University of Medical Sciences. All rights reserved

Attenuation of morphine withdrawal syndrome by various dosages of curcumin in comparison with clonidine in mouse: Possible mechanism

Background: Herbal medical compounds and their major constituent have been used in the management and treatment of opioid withdrawal syndrome and pain. This study was carried out to clarify the effect of curcumin, the major compound of turmeric, on morphine withdrawal syndrome in mouse model and its possible mechanisms of pain relieving activity by assessing in writhing test as a model of visceral pain. Methods: Due to two separate protocols (withdrawal syndrome and pain), 144 male albino mice were divided in two major groups. In withdrawal syndrome group, test effect of various dosages of curcumin (10, 20, and 40 mg/kg) was assessed on withdrawal signs and compared with positive and negative control and standard treatment (clonidine 0.4 mg/kg) groups. In pain groups, to determine the mechanism of pain relieving activity of curcumin, various dosages of curcumin (10, 20, and 40 mg/kg) in three separated groups, were used against acetic acid induced writhing (which is a constriction) test. The most effective dose (40 mg/kg) was used in writhing test and compared with groups pretreated with antagonist of major neurotransmitters involved in pain; and compared with group pretreated with vehicle (DMSO, 0.05) as control. Results: Curcumin attenuates withdrawal syndrome in a dose dependent manner in comparison with the dependent positive control group (P<0.05). It also indicated that pretreatment with naloxone and cyproheptadine significantly attenuate antinociception effect of curcumin (P<0.05). Conclusion: This study advocate that antinociception of curcumin was mediated by opioidergic and adrenergic system. © 2015, Shiraz University of Medical Sciences. All rights reserved

Protective effects of forced exercise against nicotine-induced anxiety, depression and cognition impairment in rat

Nicotine is one of the psychostimulant agents displaying parasympathomimetic activity; the chronic neurochemical and behavioral effects of nicotine remain unclear. Exercise lowers stress and anxiety and can act as a non-pharmacologic neuroprotective agent. In this study, the protective effects of exercise in nicotine withdrawal syndrome-induced anxiety, depression, and cognition impairment wereinvestigated. Methods: Seventy adult male rats were divided randomly into five groups. Group 1 served as negative control and received normal saline (0.2 mL/rat, i.p.) for 30 days, whereas group 2 (as positive control) received nicotine (6 mg/kg/day, s.c.) for the first 15 days. Groups 4, 5, and 6 were treated with nicotine (6 mg/kg/day, s.c.) for the first 15 days and then were treated with forced exercise, bupropion (20 mg/kg/day, i.p.), or a combination of the two for the following 15 days. Between day 25 and day 30, Morris water maze was used to evaluate spatial learning and memory. From days 31 to 35, the elevated plus maze (EPM), open field test (OFT), forced swim test (FST), and tail suspension test (TST) were used to investigate the level of anxiety and depression in the subjects. Results: Nicotine-dependent animals indicated a reflective depression and anxiety in a dose-dependent manner in FST, EPM, and TST, which were significantly different from the control group and also can significantly attenuate the motor activity and anxiety in OFT. Conclusions: Forced exercise, bupropion, or their combination can attenuate nicotine cessation-induced anxiety, depression, and motor activity in the mentioned behavioral assay. We conclude that forced exercise can protect the brain against nicotine withdrawal-induced anxiety, depression, and cognitive alteration. © 2016 by De Gruyter

Evaluation of anti-inflammatory and analgesic activity of the extract and fractions of Astragalus hamosus in animal models

The objective of this study was to evaluate the anti-inflammatory and analgesic activities of the hydro-alcoholic extract of the pods of Astragalus hamosus (HAAH), a plant used in Iranian traditional medicine, and antinociceptive effects of different fractions in animal models. The anti-inflammatory effect was evaluated by the rat paw edema induced by formalin. Also the analgesic effect was examined by the acetic-acid-induced writhing response and hot plate test. The analgesic effects of chloroform, hexane, ethyl acetate and aqueous fractions were evaluated by the hot-plate method. The hydroalcoholic extract of Astragalus hamosus could reduce the edema in a dose-dependent manner (P<0.05). In the acute phase, the result of 1000 mg/Kg and in the chronic phase, the result of 100 and 300 mg/Kg of the extract were more significant and comparable with the effect of sodium salicylate. Also application of different doses of HAAH had significant anti-nociceptive effects on both animal models. The findings showed that HAAH at doses of 700 and 1000 mg/Kg produced analgesic effects comparable to sodium salicylate. The hexane and ethyl acetate (but not the other fractions) showed significant analgesic activity in hot plate test, when compared to morphine. The results of this study demonstrated the anti-inflammatory and analgesic effects of HAAH extract and hexane and ethyl acetate fractions of the extract in animal models and justify traditional use of this plant in the treatment of pain and inflammatory conditions. More studies to clarify the active components are necessary. © 2015 by School of Pharmacy Shaheed Beheshti University of Medical Sciences and Health Services

Attenuation of withdrawal signs, blood cortisol, and glucose level with various dosage regimens of morphine after precipitated withdrawal syndrome in mice

Morphine withdrawal usually results in unsuccessful outcomes. Despite partial benefits from alternative substances such as methadone, its use may not lead to the desired result due to the lack of mental tranquility during the withdrawal period. In this study, by means of an animal model, morphine itself was used to manage morphine dependence. Forty mice were divided into 5 groups, in which 4 groups became dependent by increasing daily doses of morphine for 7 days (15-45 mg/kg). Afterwards, the animals received morphine for 14 days by either of the following regimens: � Once daily 45 mg/kg (positive controls) � Increasing the interval (each time 6 hours longer than the previous interval) � Irregular interval in every 36, 12 and 24 hours until the 21th day � 12, 24, 36 hours decreasing doses (each time 2.5 mg/kg less than the former dosage). Negative controls received saline solution only. On day 22, total withdrawal index (TWI) was determined by injecting 3 mg/kg of naloxone. Thereafter, blood samples were taken for the measurement of cortisol and glucose levels. TWI significantly decreased in all test groups in comparison with the positive control animals (P<0.001). Cortisol levels significantly decreased when either the dosage or the administration frequencies were decreased on a regular and gradual basis (P<0.005). Blood glucose levels significantly decreased in animals that received decreasing doses of morphine (P<0.005). This study suggests that no other measures may be required in clinical practice except for changing the dosage regimen of morphine for the cessation of self-administration. © 2016, Shiraz University of Medical Sciences. All rights reserved

Selegiline acts as neuroprotective agent against methamphetamine-prompted mood and cognitive related behavior and neurotoxicity in rats: Involvement of CREB/BDNF and Akt/GSK3 signal pathways

Objective(s): Present study investigated the neuroprotective effects of selegiline and the molecular mechanisms involved in methamphetamine-induced neurotoxicity. Materials and Methods: Male wistar rats were randomly divided into six groups (10 rats in each group). Group 1 and group 2 received normal saline and methamphetamine (10 mg/kg), respectively. Groups 3, 4, 5 and 6 were treated simultaneously with methamphetamine and selegiline. From day 22 to day 28, forced swim test, elevated plus maze, and open field test were conducted to assess mood (anxiety and depression) levels, and from day 17 to day 21, Morris Water Maze was conducted for cognition assessment. On day 29, hippocampus of the animals were isolated and evaluated by ELISA method for oxidative, antioxidant, and inflammatory factors and expression levels of active (total) and inactive (phosphorylated) forms of cyclic AMP response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), Akt (Protein Kinase B) and glycogen synthase kinase 3 (GSK3) proteins. Results: Selegiline reduced behavioral impacts caused by methamphetamine in all doses. Methamphetamine administration may improve malondialdehyde, tumor necrosis factor-alpha, interleukin-1 beta and GSK3 (both forms). Moreover, methamphetamine reduced the activity of superoxide dismutase, glutathione peroxidase, glutathione reductase, amount of BDNF, CREB and Akt (both forms). Conclusion: Current research showed that selegiline can protect the brain from methamphetamine-prompted neurodegeneration, and this could be intervened by CREB-BDNF or Akt-GSK3 signaling pathways. © 2020 Mashhad University of Medical Sciences. All rights reserved

Survival of COVID-19 patients requires precise immune regulation: The hypothetical immunoprotective role of nicotinic agonists

Summary recent studies have provided novel evidence regarding the effect of nicotine agonists on the prevention or modulation of cytokines storm and reduction of infection. In this study we tried to attempt to address these issues from a therapeutic perspective of nicotine agonists in this manner and we describe one of the most challenging theories of immunotherapy in coronavirus-19 (COVID-19). The analysis of the proposed mechanism goes beyond the physiological consequences of a way to design new strategies to provide anti-inflammatory drugs. © 2020 Elsevier Lt

Neuropathies and neurological dysfunction induced by coronaviruses

During the recent years, viral epidemic due to coronaviruses, such as SARS (Severe Acute Respiratory Syndrome), Middle East Respiratory Coronavirus Syndrome (MERS), and COVID-19 (coronavirus disese-19), has become a global problem. In addition to causing cardiovascular and respiratory lethal dysfunction, these viruses can cause neurodegeneration leading to neurological disorders. Review of the current scientific literature reveals the multiple neuropathies and neuronal dysfunction associated with these viruses. Here, we review the major findings of these studies and discuss the main neurological sequels and outcomes of coronavirus infections with SARS, MERS, and COVID-19. This article analyzes and discusses the main mechanisms of coronavirus-induced neurodegeneration according to the current experimental and clinical studies. Coronaviruses can damage the nerves directly through endovascular dysfunctions thereby affecting nerve structures and synaptic connections. Coronaviruses can also induce neural cell degeneration indirectly via mitochondrial dysfunction inducing oxidative stress, inflammation, and apoptosis. Thus, coronaviruses can cause neurological disorders by inducing neurovascular dysfunction affecting nerve structures and synaptic connections, and by inducing inflammation, oxidative stress, and apoptosis. While some of these mechanisms are similar to other RNA viruses, the neurotoxic mechanisms of COVID-19, MERS, and SARS-CoV viruses are unknown and need detailed clinical and experimental studies. © 2021, Journal of NeuroVirology, Inc

Duloxetine by modulating the Akt/GSK3 signaling pathways has neuroprotective effects against methamphetamine-induced neurodegeneration and cognition impairment in rats

Background: The neuroprotective effects of duloxetine, as an antidepressant agent, and the neurodegenerative effects of methamphetamine have been shown in previous studies. Nonetheless, their exact neurochemical and behavioral effects are still unclear. In the current study, we sought to clarify the molecular mechanisms involved in the protective effects of duloxetine against methamphetamine-induced neurodegeneration. Methods: Forty adult male rats were divided randomly into 5 groups. Group 1 was the negative control and received normal saline, Group 2 was the positive control and received methamphetamine, and Groups 3, 4, and 5 were concurrently treated with methamphetamine (10 mg/kg) and duloxetine (5, 10, and 15 mg/kg, respectively). All the treatments were continued for 21 days. Between days 17 and 21, the Morris Water Maze (MWM) was used to assess learning and memory in the treated groups. On day 22, the hippocampus was isolated from each rat and oxidative, antioxidant, and inflammatory factors were measured. Additionally, the expression levels of the total and phosphorylated forms of the Akt and GSK3 proteins were evaluated via the ELISA method. Results: Duloxetine in all the administered doses ameliorated the effects of the methamphetamine-induced cognition impairment in the MWM. The chronic abuse of methamphetamine increased malondialdehyde, tumor necrosis factor-α, and interleukin-1β, while it decreased superoxide dismutase, glutathione peroxidase, and glutathione reductase activities. Duloxetine not only prevented these malicious effects of methamphetamine but also activated the expression of Akt (both forms) and inhibited the expression of GSK3 (both forms) in the methamphetamine-treated rats. Conclusion: We conclude that the Akt/GSK3 signaling pathways might have a critical role in the protective effects of duloxetine against methamphetamine-induced neurodegeneration and cognition impairment. © 2019, Shiraz University of Medical Sciences. All rights reserved