Physiology and Pharmacology
Volume:27 Issue: 2, Jul 2023

The use of cannabis-derived compounds for medical purposes dates from more than two thousand years. Due to its psychotropic effects and cultural aspects related to the plant of origin, its benefits have been disregarded in several western countries. Nevertheless, the number of studies on Cannabis sativa, especially on clinical applications of cannabinoids, increased significantly in the latest years. Amidst the benefits of cannabis-derived compounds is pain relief. Here we review physiological, pharmacological and chemical aspects of pain management in humans with endocannabinoids, synthetic cannabinoids and phytocannabinoids. The analgesia mechanism can be explained not only through interactions with cannabinoid receptors 1 and 2 but also through direct or indirect interaction with serotonin, glycine, gamma-aminobutyric acid, N-methyl-D-aspartate, adrenergic and opioid receptors, as well as transient receptors potential channels. They can also modify the behavior of molecules such as cytokines, calcitonin gene-related protein and substance P, which largely influence pain-related mechanisms. Exogenous cannabinoids are interesting options to consider when it comes to pain management, especially in complex cases associated to poor response to the currently available drug therapy

The present study aimed to investigate the hypolipidemic and lipoprotein protective effects of a phenolic extract from sweet basil.

The antihyperlipidemic activity was evaluated using Triton WR-1339 and a highfat diet (HFD) induced hyperlipidemic mouse models. In the Triton model, plasma lipids were measured after 24h of treatment, whereas in the HFD model, body weight, food intake, plasma and fecal lipids were determined biweekly. After 45 days of treatment, the livers and abdominal adipose tissues were weighed and lipid measurements for each group were performed.

In both models, the phenolic extract at 100 and 200mg/kg significantly reduced plasma total cholesterol (TC), LDL-cholesterol (LDL-C), triglycerides, atherogenic index and LDL-C/HDL-C ratio and increased HDL-C. Besides, the phenolic extract significantly repressed the gain in body, liver and adipose tissue weights while the food intake was not significantly hindered. Moreover, phenolic extract decreases TC and triglycerides in the liver and adipose tissue and increases their fecal excretion. The phenolic extract exhibited a protective effect against plasma lipoprotein oxidation (IC50=4.64±0.42 µg/ml) and neutralized DPPH free radical (IC50=2.83±0.05 µg/ml) in a manner relatively similar to that exerted by butylated hydroxyanisole (synthetic antioxidant). Total phenolics in the extract represent 234.45±0.84 mg/g and HPLC analysis reveals that the extract includes four main phenolics, with caftaric acid being particularly abundant.

This data suggests that sweet basil is an interesting plant food rich in phenolic compounds that might significantly reduce hyperlipidemia and prevent atherosclerosis and related cardiovascular complications.

High-fat fructose diet (HFFr) consumption leads to inflammatory response and adverse metabolic consequences. Evaluating the changes in pancreatic-derived factor (PANDER) as one of the inflammatory metabolites, due to its regulatory role in glucose metabolism, could provide insight into the glucose homeostasis mechanisms.

Dams and their pups were randomly assigned to a standard diet (StD) and HFFr groups. After weaning, the male Wistar offspring were allocated to StD, StD-DMSO (Vehicle: V), StD-4-phenyl butyric acid (Drug: D), HFFrD, HFFrD-V and HFFrD-D groups, while they were on their diet for five weeks and treated for ten days. At the end of the procedure, the plasma glucose, insulin and PANDER levels, atherogenic indices and pancreatic PANDER content were determined.

HFFrD intake increased plasma glucose level and homeostasis model assessment of insulin resistance. Also, atherogenic indices were elevated through the increase of cholesterol and low-density lipoprotein and the decrease of high-density lipoprotein (HDL) in HFFrD group. An increase in both plasma and pancreatic PANDER levels was observed in the HFFrD group. The drug decreased the plasma and pancreatic PANDER levels along with plasma glucose, cholesterol and the ratio of cholesterol to HDL levels in the HFFrD group.

Since long-term HFFrD intake led to hyperglycemia, insulin resistance and dyslipidemia with an increase in plasma and pancreatic PANDER levels, and on the other hand, 4-phenyl butyric acid administration decreased PANDER levels as well as plasma glucose and cholesterol concentrations, PANDER increment may be the cause of glucose and lipid disturbances.

Carbon tetrachloride (CCl4 ) is a toxic compound since it causes acute and chronic toxicity in various tissues due to oxidative stress. On the other hand, Zataria multiflora Boiss (ZM) essential oil as a natural product has different biological effects such as antioxidant activity. Therefore, this study was carried out to assess the protective potential of ZM essential oil on possible toxicity induced by chronic administration of CCl4 in kidney tissues of rats.

Male Sprague-Dawley rats were assigned into five groups including C: control group; CO: vehicle control group; CE: rats that were given the essential oil (500µl/kg/day); F: rats that received CCl4 (1ml/kg) twice a week; and FE: rats that were given CCl4 and essential oil with the mentioned doses. After 11 weeks of study, kidney tissues were collected to measure the activity of AST, ALT, ALP, GGT and LDH enzymes and oxidative stress parameters (TAC, TBARS and GSH).

The results showed a significant increase in the activity of ALT, ALP and LDH enzymes in kidney tissues of group F compared to the control groups, probably due to defects in cell metabolism induced by CCl4 . But in FE group, essential oil due to antioxidant activity could ameliorate the mentioned parameters in comparison to group F. There was not a significant change in the level of lipid peroxidation marker in kidney tissues of group F in comparison to the control groups. Histopathological studies also did not show any significant changes among kidney tissues of groups.

Administration of CCl4 affected on the activity of some biochemical enzymes in kidney tissues but there was no oxidative stress or injury in the tissues. However, prophylactic administration of ZM Boiss essential oil had antioxidant prop-erties in modulating the measured parameters.

High fructose consumption is commonly associated with increased risk of cardiovascular disease (CVD). However, cardiovascular effects of aromatase inhibitors remain unresolved, although they are effective in the treatment of breast cancer. Thus, this study investigated the effect of letrozole on CVD indicators in Wistar rats exposed to high fructose intake.

Twenty male rats were randomly placed in four groups (n=5/group): control (distilled water), fructose (10% fructose in drinking water), letrozole (1mg/kg) and fructose+ letrozole. After 21-day exposure, fasting blood glucose was taken and the rats were sacrificed, while blood and heart were collected and prepared for biochemical analyses.

Our data showed that 10% fructose induced hyperglycaemia and lipid peroxidation. It reduced serum high-density lipoprotein cholesterol, elevated serum total cholesterol (TC), triglycerides and free fatty acid but did not alter serum low-density lipoprotein cholesterol significantly, when compared with the control. Furthermore, high fructose-intake increased serum or cardiac adenosine deaminase (ADA), xanthine oxidase and uric acid. Our findings revealed that letrozole, when taken with 10% fructose, attenuated all the observed fructoseinduced alterations. However, when administered alone, letrozole elevated serum TC as well as cardiac malondialdehyde and ADA.

This study showed that high fructose-intake promoted the risk of CVDs in rats, while administration of letrozole attenuated fructose effects. Hence, letrozole may serve as a potential adjuvant therapy for attenuating CVD risk. However, further pre-clinical and clinical findings are necessary to thoroughly investigate the cardiometabolic effects of letrozole.

The positive impact of physical activity on age-related memory impairment is well documented. There is no clear report on the effects of pre-adolescent exercise on cognitive abilities in adulthood.

Male Wistar rats (4-week-old) were randomized to a non-swimmer (control, n=20) and swimmer (n=20). The swimmer group trained for 30min a day, 6 days per week, 6 weeks. After the last day, behavior (through passive avoidance learning and radial maze) and electrophysiological techniques were evaluated in rats.

Swimming exercise led to a decrease in the number of trials in the passive avoidance test. In addition, swimming reduced the number of working memory and reference memory errors in the radial maze task. On the radial maze task, the two groups showed equal learning ability in finding the baited food arms by day 15. The results of the recall tests showed that the number of total memory errors and working memory errors was significantly lower in the swimmer group than in the non-swimmer group. Exercise also improved both Population spike (PS) amplitude and field-excited postsynaptic potential slope.

These results revealed that swimming exercise could improve memory by increasing synaptic plasticity in rats.

Stress disturbs the gut-brain axis and contributes to the development of mood disorders and memory impairment. Recent findings on the anti-stress effects of monoamine modulators have shown that the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine (Vlx) is more effective in stressed rodents. However, the effects of Vlx on microbiota and memory impairment- and stress-related behaviors are still unknown. Synbiotics (Syn), a mixture of probiotics and prebiotics, can modify the gut microbiome; however, the effects of anti-anxiety and anti-memory deficits are still not well understood. Therefore, this study proposed to compare the effectiveness of Vlx and Syn in the reduction of learned fearand memory impairment-like behaviors in an animal model of stress.

Forty male adult Wistar rats were subjected to stress by immobilization in a restrainer for 2h per day and were administered 10mg/kg Vlx and/or 2g of Syn containing 1.01010 CFU probiotic strains and prebiotic oligosaccharides daily for 14 days. Learned fear, recognition memory and locomotor activity were evaluated by the elevated-T maze, novel objective recognition and open field tests. Blood samples and adrenal glands were collected to measure the circulating corticosterone levels and relative adrenal weights, which were used as markers of stress responses.

The immobilized-stressed rats showed hyperactivity in stress responses, as demonstrated by increased relative adrenal weights and serum corticosterone levels. Both Vlx and Syn reduced the increase in serum corticosterone levels in stressed rats. Furthermore, Vlx- and/or Syn-treated stressed rats had fewer learned fear-like behaviors and a higher discrimination index without any locomotor activity changes than vehicle-treated stressed rats.

Syn supplementation had comparable effects to SNRIs in alleviating the risk of developing anxiety disorders and memory impairment in stressed individuals or psychiatric patients.

The side-effects and short anesthesia caused by ketamine limit its individual application. Moreover, the anti-inflammatory, sedative and muscle relaxant effects of borneol as an analgesic and anesthetic have promoted its application in Chinese and Japanese medicine. This study examined the effects of co-administration of borneol and ketamine on anesthesia parameters in male rats.

Twenty-four male rats were divided into four groups, and respectively received borneol (Bo), ketamine (K), borneol-ketamine (BoK) and diazepam-ketamine (DK). Parameters recorded included the heart rate, respiratory rate, body temperature and pain reflexes (ear, tail and pedal), induction time, duration of surgical anesthesia and walking time.

Borneol did not individually induce surgical anesthesia, which was reached faster in group DK than in group BoK. Insignificant differences in duration of surgical anesthesia, walking time and pain reflexes were observed between groups BoK and DK. The heart rate, respiratory rate and body temperature were higher in group BoK than in group DK.

The pre-anesthetic and hypnotic effects of borneol were similar to those of diazepam. Further studies are, however, required for determining the exact pharmacological mechanism of borneol

Estradiol has been shown to facilitate synaptic long-term potentiation (LTP) mainly through translocation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor from intracellular pool to the post synaptic membrane. On the other hand, oligomeric amyloid beta (oAβ) decreases number of AMPA receptors in the synapses. It is well known that trafficking of AMPA receptors is governed by an atypical and autonomously active isoform of PKC called protein kinase M zeta (PKMζ). In spite of these evidence, the effect of estradiol on PKMζ expression is not yet studied. We aim to examine the possible protective effect of estradiol on PKMζ and AMPA receptor subunits against oAβ in hippocampal primary cell culture.

Primary cell culture was prepared from postnatal (P0 to P3) rat pups. They were decapitated and the brains were removed. Hippocampi were isolated and collected in cold phosphate buffer saline. Then, they were trypsinized at 37°C for 15min. The cells were treated with 1µM OAβ or vehicle for 24h and then with 100nM estradiol for another 24h. Using the western blot analysis, the expression level of AMPAR subunit glutamate receptor 1 (GluA1), GluA2 and PKMζ were determined.

OAβ decreased the level of GluA1, GluA2 and PKMζ. Estradiol did not change the molecule levels in healthy cells; however, it preserved their expression levels in OAβ treated cells.

These findings suggest that estradiol may restore expression level of synapse related molecules in an Alzheimer’ disease cell model, in part, through acting on PKMζ signaling pathway.

Breast cancer (BC) is the second leading cause of cancer deaths in the world. Studies suggest that the lysophosphatidic acid (LPA) gene is the cause of invasion and metastasis in malignant cancers, including BC. In addition, the PI3K/ PAK1/ ERK cascade in cancer cells helps metastatic BC. It has been observed that LPA can stimulate reactive oxygen species production, which is an important mediator of LPA to stimulate the migration of BC cells and activate the PI3K/ PAK1/ ERK signaling pathway.

This study aimed to evaluate the Lactobacillus brevis probiotic supernatant’s effectiveness in reducing LPA expression in BC cell lines. MCF-7 and MDA-MB-231 cell lines were treated with supernatant of local Lactobacillus brevis for 24 and 48h. mRNA expression levels of LPAR1 and LPAR2 genes were evaluated by qRT-PCR. Furthermore, an invasion assay was performed to assess these cell lines’ invasion rate following treatment.

The results indicated a remarkable decline in the survival rate of treated cells. LPAR1 and LPAR2 gene expression declined in MDA-MB-231 and MCF-7 cells. Moreover, the invasion rate of these cells was reduced following treatment.

Considering Lactobacillus brevis supernatant’s cytotoxic effects on cancerous cells, this bacteria could be thought of as a promising application for a possible treatment approach with fewer adverse reactions. However, more research is obviously needed. In the future, probiotics could be used in conjunction with currently available therapies.