Abir T. El-Alfy

Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.

The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Delta(9)-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Delta(9)-THC and Delta(8)-THC showed a U-shaped dose response with only Delta(9)-THC showing significant antidepressant-like effects at 2.5 mg/kg (p<0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200mg/kg, respectively (p<0.01). The antidepressant-like action of Delta(9)-THC and CBC was further confirmed in the TST. Delta(9)-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p<0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p<0.01). Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.

Neurobehavioral and transcriptional effects of acrylamide in juvenile rats.

Acrylamide is a type-2 alkene monomer with established human neurotoxic effects. While the primary source of human exposure to acrylamide is occupational, other exposure sources include food, drinking water, and smoking. In this study, neurobehavioral assays coupled with transcriptional profiling analysis were conducted to assess both behavioral and gene expression effects induced by acrylamide neurotoxicity in juvenile rats. Acrylamide administration in rat pups induced significant characteristic neurotoxic symptoms including increased heel splay, decrease in grip strength, and decrease in locomotor activity. Transcriptome analysis with the Affymetrix Rat Genome 230 2.0 array indicated that acrylamide treatment caused a significant alteration in the expression of a few genes that are involved in muscle contraction, pain, and dopaminergic neuronal pathways. First, expression of the Mylpf gene involved in muscle contraction was downregulated in the spinal cord in response to acrylamide. Second, in sciatic nerves, acrylamide repressed the expression of the opioid receptor gene Oprk1 that is known to play a role in neuropathic pain regulation. Finally, in the cerebellum, acrylamide treatment caused a decrease in the expression of the nuclear receptor gene Nr4a2 that is required for development of dopaminergic neurons. Thus, our work examining the effect of acrylamide at the whole-genome level on a developmental mammalian model has identified a few genes previously not implicated in acrylamide neurotoxicity that might be further developed into biomarkers for assessing the risk of adverse health effects induced by acrylamide exposure.

Secondary metabolites from three Florida sponges with antidepressant activity.

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.

Naturally Occurring and Related Synthetic Cannabinoids and their Potential Therapeutic Applications

Naturally occurring cannabinoids (phytocannabinoids) are biosynthetically related terpenophenolic compounds uniquely produced by the highly variable plant, Cannabis sativa L. Natural and synthetic cannabinoids have been extensively studied since the discovery that the psychotropic effects of cannabis are mainly due to Delta(9)-THC. However, cannabinoids exert pharmacological actions on other biological systems such as the cardiovascular, immune and endocrine systems. Most of these effects have been attributed to the ability of these compounds to interact with the cannabinoid CB1 and CB2 receptors. The FDA approval of Marinol, a product containing synthetic Delta(9)-THC (dronabinol), in 1985 for the control of nausea and vomiting in cancer patients receiving chemotherapy, and in 1992 as an appetite stimulant for AIDS patients, has further intensified the research interest in these compounds. This article reviews patents (2003-2007) that describe methods for isolation of cannabinoids from cannabis, chemical and chromatographic methods for their purification, synthesis, and potential therapeutic applications of these compounds.

Towards a better understanding of the psychopharmacology of nutmeg: Activities in the mouse tetrad assay

ETHNOPHARMACOLOGICAL RELEVANCE Nutmeg, the seeds of Myritica fragrans (family Myristicaceae), is a well known kitchen spice with a long-standing reputation as a psychoactive herb. Nutmeg at high doses is considered a cheap substitute to several drugs of abuse. Earlier reports have attributed amphetamine-like activities to nutmeg. AIM OF THE STUDY To characterize the neuropharmacological effects of different nutmeg extracts, administered orally and intraperitoneally, in comparison to Delta(9)-terahydrocannabinol, amphetamine, and morphine. MATERIALS AND METHODS Methanolic (ME), dichloromethane (DE), and hexane (HE) extracts were obtained from a chromatographically fingerprinted batch of nutmeg. Biological evaluation was conducted in sets of 6-8 mice in the tetrad assay at doses ranging from 100 to 500 and 500 to 1000 mg/kg for i.p. and oral administration, respectively. RESULTS While oral administration of all the nutmeg extracts at 500 mg/kg caused a significant increase in locomotor activity, the i.p. administration of DE showed significant reduction in rectal temperature along with a significant increase in tail flick latency at 300 mg/kg. A significant decrease in core body temperature was observed with HE at 100 mg/kg, while higher doses caused significant increases in hot plate latency. CONCLUSION Different behavioral effects were observed that varied by the type of extract as well as by the route of administration.

Identification of antidepressant drug leads through the evaluation of marine natural products with neuropsychiatric pharmacophores.

The marine environment is a valuable resource for drug discovery due to its diversity of life and associated secondary metabolites. However, there is very little published data on the potential application of marine natural products to treat neuropsychiatric disorders. Many natural products derived from chemically defended organisms in the marine environment have pharmacophores related to serotonin or clinically utilized antidepressant drugs. Therefore, in the present study, compounds selected for their structural similarity to serotonin or established antidepressants were evaluated for antidepressant-like activity using the forced swim and tail suspension tests in mice. The antidepressant positive controls, citalopram (selective serotonin reuptake inhibitor) and despiramine (tricyclic antidepressant) both dose-dependently reduced immobility time in the forced swim and tail suspension tests. Two marine natural product compounds tested, aaptamine and 5,6-dibromo-N,N-dimethyltryptamine, also produced significant antidepressant-like activity in the forced swim test. In the tail suspension test, the antidepressant-like effects of 5,6-dibromo-N,N-dimethyltryptamine were confirmed, whereas aaptamine failed to produce significant results. None of the tested compounds induced hyperlocomotion, indicating that nonspecific stimulant effects could not account for the observed antidepressant-like actions of the compounds. These studies highlight the potential to rationally select marine derived compounds for treating depression and other neuropsychiatric disorders.

Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa

Seven new naturally occurring hydroxylated cannabinoids (1-7), along with the known cannabiripsol (8), have been isolated from the aerial parts of high-potency Cannabis sativa. The structures of the new compounds were determined by 1D and 2D NMR spectroscopic analysis, GC-MS, and HRESIMS as 8α-hydroxy-Δ(9)-tetrahydrocannabinol (1), 8β-hydroxy-Δ(9)-tetrahydrocannabinol (2), 10α-hydroxy-Δ(8)-tetrahydrocannabinol (3), 10β-hydroxy-Δ(8)-tetrahydrocannabinol (4), 10α-hydroxy-Δ(9,11)-hexahydrocannabinol (5), 9β,10β-epoxyhexahydrocannabinol (6), and 11-acetoxy-Δ(9)-tetrahydrocannabinolic acid A (7). The binding affinity of isolated compounds 1-8, Δ(9)-tetrahydrocannabinol, and Δ(8)-tetrahydrocannabinol toward CB1 and CB2 receptors as well as their behavioral effects in a mouse tetrad assay were studied. The results indicated that compound 3, with the highest affinity to the CB1 receptors, exerted the most potent cannabimimetic-like actions in the tetrad assay, while compound 4 showed partial cannabimimetic actions. Compound 2, on the other hand, displayed a dose-dependent hypolocomotive effect only.

Nature Against Depression

Depression is a major health problem currently recognized as a leading cause of morbidity worldwide. In the United States alone, depression affects approximately 20% of the population. With current medications suffering from major shortcomings that include slow onset of action, poor efficacy, and unwanted side effects, the search for new and improved antidepressants is ever increasing. In an effort to evade side effects, people have been resorting to popular traditional herbal medicines to relieve the symptoms of depression, and there is a need for more empirical knowledge about their use and effectiveness. This review provides an overview of the current knowledge state regarding a variety of natural plant products commonly used in depression. Herbal medicines discussed that have been used in clinical trials for the treatment of mild to moderate depression states include the popular St. Johns wort, saffron, Rhodiola, lavender, Echium, and the Chinese formula banxia houpu. In addition, new emerging herbal products that have been studied in different animal models are discussed including Polygala tenuifolia, the traditional Chinese herbal SYJN formula, gan mai da zao, and Cannabis sativa constituents. A comprehensive review of the chemical, pharmacological, and clinical aspects of each of the reviewed products is provided. Finally, recent preclinical studies reporting the antidepressant action of marine-derived natural products are discussed at the end of the review.

Effect of cortisol and urea on flavin monooxygenase activity and expression in rainbow trout, Oncorhynchus mykiss.

Expression of flavin-containing monooxygenase(s) (FMO) correlates with salinity exposure in certain species of euryhaline fish, such as the rainbow trout, Oncorhynchus mykiss. The mechanism(s) by which salinity regulates FMO is unclear. Adult rainbow trout were infused through the dorsal aorta with either cortisol or urea. At 500 ng/ml, cortisol caused a significant increase in FMO-catalyzed thiourea oxidase activity in gill and liver microsomes. FMOI expression, however, was significantly increased by the high cortisol dose only in gill microsomes. The levels of TMAO and urea were not altered by cortisol. In the liver, urea infusion caused an increase in hepatic FMO activity. FMO expression and activity correlated with elevated tissue urea levels, but TMAO concentrations were not related. These results indicate that FMO expression and activity may be partially controlled by the osmoregulatory/stress hormone. cortisol, and concentrations of the organic osmolyte, urea, in the rainbow trout.

Amelioration of the cardiovascular manifestations of the yellow scorpion Leiurus quinquestriatus envenomation in rats by red grape seeds proanthocyanidins

The study attempts to determine the involvement of oxidative stress in cardiovascular manifestations during Leiurus quinquestriatus quinquestriatus (LQQ) scorpion envenomation and to examine the possible protective role of red grape seed proanthocyanidins (GSP) against such effects. Lethality studies conducted in mice demonstrated a significant (p<0.01) protection of GSP against venom lethality. Pretreatment with GSP (200 mg kg(-1), p.o., 10 days) prior to venom injection (350 microg kg(-1), s.c.) resulted in a significant decrease in percent mortality as well as in significant prolongation of the animals survival time (p<0.01). Monitoring the cardiovascular effects elicited by venom injection in anesthetized rats revealed a marked protection of GSP against the increase in mean arterial blood pressure evoked by LQQ venom. Moreover, pretreatment with GSP reduced the characteristic signs of conduction defects, myocardial ischemia, and infarction observed by venom injection. Biochemical analyses showed that scorpion envenomation caused significant (p<0.001) elevation in serum lactate dehydrogenase as well as creatine kinase-MB activities. Such elevation was ameliorated by GSP (p<0.001). Oxidative stress parameters revealed that scorpion venom significantly increased (p<0.001) the level of lipid peroxidative damage in cardiac tissues and reduced the activity of both glutathione reductase and glutathione peroxidase enzymes in cardiac tissues (p<0.05). In the meantime, GSP offered significant protection against lipid peroxidative damage (p<0.05) and enhanced cardiac glutathione reductase activity (p<0.001). In summary, the current study demonstrates that pretreatment with GSP offers significant protection against LQQ envenomation possibly via enhancement of the antioxidant defense systems.