Neurobehavioral protective effects of Japanese sake yeast supplement against chronic stress-induced anxiety and depression-like symptoms in mice: Possible role of central adenosine receptors.

RATIONALE: Using routine synthetic drugs in the treatment of psychiatric disorders may have some restrictions due to serious side effects and pharmacoresistance. Some natural agents may be promising alternatives in this case. The neuroprotective activity of the neuromodulator adenosine and its receptor, A1 receptor (A1R) in the central nervous system has been mentioned in different studies. OBJECTIVE: We aimed to determine the anxiolytic, antidepressant and sedative effects of Japanese sake yeast as the first report. METHOD: Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose levels of 100, 200 and 300 mg kg-1 once daily for a week. The anxiolytic, antidepressant, and sedative actions of sake yeast were evaluated with the related tests. RESULTS: In all dose regiments, sake yeast significantly improved functions in the EPM and FST. 200 and 300 mg/kg of sake yeast significantly increased sleep duration and reduced sleep latency. Anxiolytic and antidepressant-like activities of sake yeast were maintained by the injection of ZM241385 (15 mg kg-1), a selective adenosine A2AR antagonist but completely counteracted by the injection of 8-cyclopentyltheophylline (10 mg kg-1), a selective adenosine A1R antagonist. 300 mg/kg of the yeast significantly increased the BDNF levels. Amygdala corticosterone levels did not show any significant changes at any dosage. Amygdala TNF-α, IL-6 and IL-1ß levels also decreased significantly with all the sake regiments compared to the control group. CONCLUSIONS: We conclude that oral sake yeast supplement exerts a neurobehavioral protective effect predominantly by activating central A1Rs.

Reversal of chronic restraint stress-induced memory impairment by Japanese sake yeast supplement in mice: Role of adenosine A1 and A2A receptors.

Controversial studies indicate the adenosine compound (a neuromodulator with neuroprotective activity) intervention on cognitive performance. On the other hand, Japanese sake yeast has been enriched with oral adenosine analogs as a novel natural agent. As the first report, we aimed to evaluate the effects of Japanese sake yeast supplement in a mouse model of chronic restraint stress-induced cognitive dysfunction. Mice were subjected to a one-week stress protocol and concomitantly treated orally with sake yeast at the dose level of 100, 200 and 300 mg/kg once daily for a week. The spatial and conditioned fear memory functions were evaluated with the Morris Water Maze (MWM) and the Passive Avoidance Learning (PAL) test, respectively. In all dosing regimens, improvements in spatial cognition were observed significantly in the MWM. 200 and 300 mg/kg of sake yeast significantly improved short- and long-term fear memory functions in the PAL test. Memory-enhancing effect of sake yeast was potentiated by the injection of ZM241385 (15 mg/kg), a selective adenosine A2A receptor (A2AR) antagonist, but completely disappeared by the injection of 8-cyclopentyltheophylline (CPT-8, 10 mg/kg), a selective adenosine A1 receptor (A1R) antagonist. The findings of the present study demonstrate the efficacy of sake yeast in acting as a cognitive performance-enhancing agent. Eventually, sake yeast and its ingredient S-adenosyl methionine (SAM) may be useful in improving memory in patients suffering from many dementia forms including Alzheimer's disease (AD).

The effect of tetrahydrocannabinol:cannabidiol oromucosal spray on cognition: a systematic review.

PURPOSE: Previous studies have shown that tetrahydrocannabinol (THC), the main psychoactive component of cannabis, can impair cognitive abilities. There is also some evidence that cannabidiol (CBD), the most abundant non-intoxicating constituent of cannabis, can attenuate these effects. The purpose of this study was to investigate the effects of THC:CBD oromucosal spray (with equal parts THC and CBD) on cognition compared with control conditions in human studies. METHODS: A systematic literature search was performed on four major bibliographic databases. Studies were included in the present review if they evaluated the cognitive effects of THC:CBD oromucosal spray compared with a control condition. RESULTS: Ten studies were identified (7 on patients with multiple sclerosis, 1 on those with Huntington, and 2 on healthy volunteers) with 510 participants in total. There was considerable heterogeneity among the studies in terms of dose and duration of administration. All studies have used an equal or nearly equal dose of THC and CBD. CONCLUSIONS: Although the results across studies were somewhat inconsistent, most evidence revealed that there is no significant difference between THC:CBD oromucosal spray and control treatments in terms of cognitive outcomes. However, more trials are needed with longer follow-up periods, and dose considerations, particularly comparing lower and higher doses of the spray.

Effectiveness of crocin of saffron (Crocus sativus L.) against chemotherapy-induced peripheral neuropathy: A randomized, double-blind, placebo-controlled clinical trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Chemotherapy-induced peripheral neuropathy (CIPN) is one of the complications vexes patients treated with anti-cancer agents. Saffron has been demonstrated to attenuate symptoms of peripheral neuropathy in animal models. Also, there is a published clinical trial that investigated the pain relieving effect of saffron following nationally accepted rules and concluded that saffron was successful in alleviating pain symptoms in patients suffering from fibromyalgia. AIM OF THE STUDY: We aimed to determine the efficacy of crocin as a constituent of saffron in CIPN as the first report. MATERIALS AND METHODS: One hundred and seventy-seven enrolled eligible patients (between December 2018 and March 2020) for study entry were cases demonstrating mild to severe symptomatic CIPN for at least a month. These cases were randomly assigned to two main groups including 15 mg crocin tablet, bid (30 mg total daily target dose) and placebo tablet for 8 weeks. A crossover study was performed with a 2-week washout period. Patient outcomes were measured once a week for 8 consecutive weeks. RESULTS: Grade of sensory, motor and neuropathic pain decreased considerably and significantly in the crocin group compared with placebo (P < 0.05). Observed toxicities were mild and adverse effects had no significant differences between the two groups (P > 0.05). CONCLUSIONS: Crocin considerably seems to be effective for relieving symptoms of CIPN in cancer patients receiving chemotherapy agents. However, further studies are needed about crocin with its beneficial neuropharmacological effects and lower adverse effects than the chemical agents such as antidepressants, lamotrigine, and gabapentin.

Dexmedetomidine as an Analgesic Agent with Neuroprotective Properties: Experimental and Clinical Aspects.

Dexmedetomidine (Dexdor or Precedex®) is considered as a sedative agent which is widely used as an adjuvant in general anesthesia and critical care practice. There is extensive evidence indicating its neuroprotective properties especially in various ischemic and hemorrhagic brain injury models of animals. Clinical trials have shown that dexmedetomidine (DEX) can improve the outcome of intensive care unit (ICU) patients. Also, DEX is appropriate as a non-opioid analgesic therapy whenever minimizing opioid-related side effects is necessary. The present article reviews the recent advances in the use of DEX as a neuroprotective agent in both animal and human studies including newest findings about the mechanism of the drug as well as analgesic efficacy of this drug at all perioperative stages. In spite of the beneficial effects of the drug on the nervous system, there are potential adverse effects, such as hypotension and bradycardia, which can be treated pharmacologically and must be taken into consideration by clinicians.

Safety and Efficacy of Dexmedetomidine in Breast Surgeries: A Systematic Review and Meta-Analysis.

PURPOSE: Pain control during and after breast surgery is still a challenging task. Dexmedetomidine (DEX) is considered as a sedative agent that is widely used perineurally or intravenously as an adjuvant in general anesthesia and critical care medicine practice. The aim of this study is to evaluate the efficacy of perineural DEX and intravenous (IV) DEX and their effects on postoperative complications in breast surgeries. DESIGN: Systematic review and meta-analysis. METHODS: The present study systematically reviewed all identified randomized controlled trials for efficacy and safety of IV and perineural use of DEX in breast surgeries. Databases were searched for articles published before October 2019. FINDINGS: Twelve trials were identified including 803 patients undergoing breast surgery. Although administration of IV DEX and its use with pectoral nerve (Pecs) block significantly postponed time for first analgesic request and decreased pain score at 1 and 12 hours after surgery, paravertebral use of DEX had no statistically significant effect. Pooled data about perineural DEX showed no significant effect on postoperative nausea and vomiting (PONV), whereas IV DEX significantly reduced PONV. Pooled analysis also showed that DEX administration did not significantly affect postoperative complications, such as postoperative itching, bradycardia, and pneumothorax in patients undergoing breast surgery. CONCLUSIONS: The results showed that unlike paravertebral DEX, both DEX use with Pecs blocks and IV DEX were effective in control of postoperative pain in patients undergoing breast surgeries. Unlike perineural DEX, IV DEX significantly reduced PONV.

Intracerebroventricular administration of N-type calcium channel blocker ziconotide displays anticonvulsant, anxiolytic, and sedative effects in rats: A preclinical and pilot study.

OBJECTIVE: Ziconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects. METHODS: To evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 µg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 µg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay. RESULTS: In all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control. CONCLUSION: Ziconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.

Antidepressant-like and memory-enhancing effects of the N-type calcium channel blocker ziconotide in rats.

The lack of oral or injectable formulations of ziconotide (ω-conotoxin peptide), a novel analgesic agent, limits research on potential neurobehavioral protective properties of this substance, including antidepressant-like effects. Here we expose rats to a stress paradigm that induces depression and memory impairment to assess the effects of ziconotide treatment. Ziconotide was administered intracerebroventricular (i.c.v.) to rats undergoing stereotaxic surgery at a single dose (1 µg/rat) or in repeated long-term applications (dosage groups: 0.1, 0.3, and 1 µg/rat). The antidepressant activity and memory-enhancing effects of ziconotide were examined via the forced swimming test, the Morris water maze test, and the passive avoidance learning test. Behavioral results showed that long-term i.c.v. ziconotide administration significantly decreased the immobility time and delayed the latency period to immobility in a dose-dependent manner compared to controls. In the passive avoidance learning test, the latency period increased, and in the Morris water maze test, the platform location latency time decreased. A single dose of ziconotide (1 µg/rat) did not show a significant effect on memory function or depression parameters during the same tests. Animals were sacrificed immediately after behavioral testing, and both hippocampi were removed and prepared for BDNF evaluation. Hippocampal BDNF levels were significantly increased in rats receiving long-term i.c.v. ziconotide compared to controls. Our results suggest that long-term consumption of ziconotide may attenuate the severity of depression-like behavior and could be useful for preventing memory impairments in various learning models by elevating BDNF levels.

Eucalyptus camaldulensis properties for use in the eradication of infections.

Eucalyptus camaldulensis (E. camaldulensis), called the eucalyptus has so many characteristics such as antimicrobial features. Common names include red gum, red chewing gum, river chewing gum, red chewing gum. Its class is Eucalyptus, which is comprised of 800 species worldwide, but three or four species are found in Australia. This tree generally grows on the edge of rivers with continuous or seasonal water. Most of the gray clay soils run along the riverside and are exposed to frequent floods, and clay content can save more water into the tree. Pharmacy departments and research groups have focused their attention on the cultivation and production of medicinal plants in many countries. Since plants, due to their particular nature, have inevitable the presence of certain defense mechanisms and antimicrobial agents in the form of androgens, they can be considered as a potential source of antimicrobial compounds. The active ingredient of these plants is primarily alkaloids, flavonoids, pigments, phenolics, terpenes, starches, steroids and essential oils. Recent studies have exhibited its antimicrobial effects against bacterial, fungal, parasitic and viral agents. In this study the effects against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Acinetobacterbaumannii, Streptococcus pyogenes, Proteus vulgaris, Salmonella typhi, Shigella spp., Candida albicans, Candida parapsilosis, Anopheles stephensi, Aedes aegypti, A. aegypti, A. albopictus, Culex pipiens, Trypanosoma brucei, Leishmania major, Trichomonas. Vaginalis, poliovirus type 1, coxsackie virus B, echovirus 6, West Nile Virus, herpes virus type 1, HSV-1 virus, Fusarium spp., Aspergillus flavus, Aspergillus niger, C. albicans, Alternaria alternata, Setosphaeria turcica and Magnaporthe grisea was revealed.

Effect of tetracaine on intraocular pressure in normal and hypertensive rabbit eyes.

PURPOSE: To evaluate the effect of tetracaine on intraocular pressure (IOP) in normal and hypertensive rabbit eyes. METHODS: The study was conducted on 12 healthy rabbits as controls and 6 healthy rabbits in which an experimental model of ocular hypertension (OHT) was induced by administration of 70 mL/kg of tap water through an orogastric tube. One drop of tetracaine was instilled in the left eye while a drop of normal saline (placebo) was applied to the right eye of the control group. IOP was measured before and 0, 5, 10, 15, 20, 25, 30, 35 and 40 minutes after drop administration in this group. The OHT group also received one drop of tetracaine and normal saline in the left eyes and right eyes respectively, immediately after water loading; the instillation of drops was repeated after 55 minutes. IOP was measured before and 0, 5, 10, 15, 20, 25, 30, 35, 40, 55, 70, 85, 100 and 115 minutes after water loading in this group. RESULTS: Tetracaine treated eyes in both groups (ocular hypertensive and normal controls) demonstrated significant IOP reduction at time zero (immediately after drop instillation) which was sustained up to 20 minutes, as compared to placebo treated eyes (P<0.05). In ocular hypertensive rabbits, repeat instillation of tetracaine significantly reduced IOP at 55 minutes up to 30 minutes thereafter. CONCLUSION: Topical tetracaine can reduce IOP; this fact should be considered in experiments evaluating IOP reducing agents.