Underlying Mechanisms of Anti-spasmodic, Antidiarrheal, Antioxidant and Acute Toxicity Assessments of Aqueous Extract of Mentha Suaveolens Ehrh and its Fourier Transform Infra-red Spectroscopy Analysis

Objective: The aim of this present study is to investigate the antidiarrheal, spasmolytic and antioxidant activities of aqueous extract of Mentha suaveolens Ehrh (AEMS), to study their underlying mechanisms in animal models and to reveal its main functional groups using Fourier Transform Infra-Red Spectroscopy (FTIR). Methods: Mentha suaveolens Ehrh was studied for antidiarrheal activity on Wistar rats of both sexes at the doses of 200 and 800 mg/kg body weight using castor oil-induced diarrhea, castor oil-induced enteropooling and small intestinal transit models. The extract was studied for antispasmodic property in isolated rabbit jejunum using various spasmogenic agents including Ach (10-5M), KCl (100 mM) and in the absence and in the presence of L-NAME (10-4 M) and the methylene blue (10-5 M).The antioxidant capacity of AEMS was carried out using DPPH radical scavenging activity and the ferric reducing antioxidant potential (FRAP). Ascorbic acid and Butylated HydroxyToluene (BHT) were used as references. The functional chemical groups were determined by FTIR. Results: The great antidiarrheal potential of AEMS seems to be mediated through calcium antagonism. The marked and concentration-dependent induced spasmolytic effect of AEMS appears to involve Ca2+ voltage channel blockade and the NO/cGMP pathway activation. AEMS possessed strong and concentration-dependent antioxidant potency using DPPH and FRAP. Polyphenols, carboxyl and carbohydrates were found to be the main functional groups in the AEMS analyzed by FTIR. Conclusion: Overall, our current findings provide scientific proves in animal models for the traditional use of AEMS in folk medicine for the prevention or the treatment of gastrointestinal diseases in Morocco.

Relaxation Effect of Patchouli Alcohol in Rat Corpus Cavernous and Its Underlying Mechanisms

In this study, we investigated the relaxation effect and mechanisms of patchouli alcohol (PA) on rat corpus cavernosum. Corpus cavernosum strips were used in organ baths for isometric tension studies. The results showed that PA demonstrated concentration-dependent relaxation effect on rat corpus cavernosum. The relaxant response to PA was not influenced by tetrodotoxin and atropine while it was significantly inhibited by removal of endothelium. L-NG-nitroarginine methyl ester (L-NAME, a nitric oxide synthase inhibitor) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor) significantly inhibited relaxation response to PA, whereas indomethacin (COX inhibitor) had no effect on PA-induced relaxation. The treatment of endothelium-deprived corpus cavernosum with several potassium channel blockers including tetraethylammonium (TEA), 4-aminopyridine (4-AP), and glibenclamide had no effect on PA-induced relaxation. Endothelium-deprived corpus cavernosal contractions induced by cumulative addition of Ca2+ to high KCl solution without CaCl2 were significantly inhibited by PA. Also, PA improved relaxant capacity of sildenafil in rat corpus cavernosum. In addition, the perfusion with PA significantly increased the levels of cGMP and expression of mRNA and protein of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, intracavernous injection of PA enhanced the rise in intracavernous pressure in rats during cavernosal nerve electric stimulation. In conclusion, PA relaxed the rat corpus cavernosum attributed to both endothelium-dependent and -independent properties. While the former component was mostly involved in nitric oxide signaling pathway, the endothelium-independent mechanism involved in PA-induced relaxation was probably linked to calcium antagonism.

A Prospective Repurposing of Dantrolene as a Multitarget Agent for Alzheimer’s Disease

The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer’s disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection.

Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty

Prenylamine, an antianginal agent marketed since early 1960, became the first casualty of QT interval related proarrhythmias in 1988 when it was withdrawn from the market. The period of its synthesis and marketing is of particular interest since it antedated, first, any serious clinical safety concern regarding drug-induced prolongation of the QT interval which was, in fact, believed to be an efficient antiarrhythmic mechanism; second, the first description of torsade de pointes as a unique proarrhythmia, typically associated with prolonged QT interval; and third, the discovery and recognition of calcium antagonism as an important cardiovascular therapeutic strategy. This review, 30 years almost to the day following its withdrawal, provides interesting perspectives on clinical, pharmacological and regulatory outcomes that followed. Prenylamine underscored torsadogenic potential of other early antianginal drugs on the market at that time and identified QT-related proarrhythmias as a much wider major public health issue of clinical and regulatory concern. This resulted in various guidelines for early identification of this potentially fatal risk. Application of these guidelines would have readily identified its proarrhythmic potential. Prenylamine also emphasized differences in drug responses between men and women which subsequently galvanized extensive research into sex-related differences in pharmacology. More importantly, however, investigations into the mechanisms of its action paved the way to developing modern safe and effective calcium antagonists that are so widely used today in cardiovascular pharmacotherapy.