Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified. The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression. Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography–mass spectrometry. At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. −45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment. The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.

Hypertension is considered a major public health issue due to its high prevalence and subsequent risk of cardiovascular and kidney diseases. Thus, the search for new antihypertensive compounds remains of great interest. Snake venoms provide an abundant source of lead molecules that affect the cardiovascular system, which makes them prominent from a pharmaceutical perspective. Such snake venom components include bradykinin potentiating peptides (proline-rich oligopeptides), natriuretic peptides, phospholipases A₂, serine-proteases and vascular endothelial growth factors. Some heparin binding hypotensive factors, three-finger toxins and 5′ nucleotidases can also exert blood pressure lowering activity. Great advances have been made during the last decade regarding the understanding of the mechanism of action of these hypotensive proteins. Bradykinin potentiating peptides exert their action primarily by inhibiting the angiotensin-converting enzyme and increasing the effect of endogenous bradykinin. Snake venom phospholipases A₂ are capable of reducing blood pressure through the production of arachidonic acid, a precursor of cyclooxygenase metabolites (prostaglandins or prostacyclin). Other snake venom proteins mimic the effects of endogenous kallikrein, natriuretic peptides or vascular endothelial growth factors. The aim of this work was to review the current state of knowledge regarding snake venom components with potential antihypertensive activity and their mechanisms of action.

A high performance liquid chromatographic method was developed for the simultaneous determination of the related substances (R-ivabradine, dehydro-S-ivabradine, N-demethyl-S-ivabradine, ((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene-7-yl-methyl)-methyl-amine) and 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-on-3-yl)-3-chloro-propane) of the heart-rate lowering drug, ivabradine. The separation capability of seven different polysaccharide-type chiral columns (Lux Amylose-1, Lux i-Amylose-1, Lux Amylose-2, Lux Cellulose-1, Lux Cellulose-2, Lux Cellulose-3 and Lux Cellulose-4) was investigated with a mobile phase consisting of 0.1% diethylamine in methanol, 2-propanol and acetonitrile. During the screnning experiments the best results were obtained on Lux Cellulose-2 (based on cellulose tris(3-chloro-4-methylphenylcarbamate) column with methanol with an ideal case, where all the impurities eluted before the S-ivabradine peak. Chromatographic parameters (flow rate, temperature and mobile phase constituents) were optimized by a full factorial screening design. Using optimized parameters (Lux Cellulose-2 column with 0.06% (v/v) diethylamine in methanol/acetonitrile 98/2 (v/v) with 0.45 mL/min flow rate at 12 °C) baseline separations were achieved between all compounds. The optimized method was validated according to the International Council on Harmonization Q2(R1) guideline and proved to be reliable, linear, precise and accurate for determination of at least 0.05% for all impurities in S-ivabradine samples. Method application was tested on a commercial tablet formulation and proved to be suitable for routine quality control of both chiral and achiral related substances of S-ivabradine.

In addition to the classically accepted pathophysiological features of Alzheimer’s disease (AD), increasing attention is paid to the role of the insulin-resistant state of the central nervous system. Glucagon-like peptide-1 receptor (GLP-1R) agonism demonstrated neuroprotective consequences by mitigating neuroinflammation and oxidative damage. The present review aims to offer a comprehensive overview of the neuroprotective properties of GLP-1R agonists (GLP-1RAs), with a particular focus on experimental animal models of AD. Ameliorated amyloid-β plaque and neurofibrillary tangle formation and deposition following exenatide, liraglutide, and lixisenatide treatment was confirmed in several models. The GLP-1RAs studied alleviated central insulin resistance, as evidenced by the decreased serine phosphorylation of insulin receptor substrate 1 (IRS-1) and restored downstream phosphoinositide 3-kinase/RAC serine/threonine–protein kinase (PI3K/Akt) signaling. Furthermore, the GLP-1RAs influenced multiple mitogen-activated protein kinases (extracellular signal-regulated kinase: ERK; c-Jun N-terminal kinase: JNK, p38) positively and suppressed glycogen synthase kinase 3 (GSK-3β) hyperactivation. A lower proportion of reactive microglia and astrocytes was associated with better neuronal preservation following their administration. Finally, restoration of cognitive functions, particularly spatial memory, was also observed for semaglutide and dulaglutide. GLP-1RAs, therefore, hold promising disease-modifying potential in the management of AD.

Cannabidiol (CBD) showed anticonvulsant action in several preclinical models and is currently approved by regulatory agencies to treat childhood epilepsy syndromes. However, CBD treatment has limited benefits, and its long-term effects on cognition are not fully understood yet. This study aimed to examine the impact of long-term CBD treatment in the pentylenetetrazole (PTZ)-kindling model of epilepsy. Adult male Wistar rats (N = 24) received PTZ (35 mg/kg intraperitoneally) every other day until two consecutive generalized seizures occurred. CBD (60 mg/kg body weight) was administered daily by the oral route until the kindled state was achieved (n = 12). To confirm that the formulation and administration techniques were not of concern, liquid chromatography–mass spectrometry was performed to test the brain penetration of the CBD formula. As a result of CBD treatment, a lower mortality rate and significantly prolonged generalized seizure latency (925.3 ± 120.0 vs. 550.1 ± 69.62 s) were observed, while the frequency and duration of generalized seizures were not influenced. The CBD-treated group showed a significant decrease in vertical exploration in the open field test and a significant decrease in the discrimination index in the novel object recognition (NOR) test (−0.01 ± 0.17 vs. 0.57 ± 0.15, p = 0.04). The observed behavioral characteristics may be connected to the decreased thickness of the stratum pyramidale or the decreased astrogliosis observed in the hippocampus. In conclusion, CBD treatment did not prevent kindling, nor did it affect seizure frequency or duration. However, it did increase the latency to the first seizure and decreased the prolonged status epilepticus-related mortality in PTZ-kindled rats. The cognitive impairment observed in the NOR test may be related to the high dose used in this study, which may warrant further investigation.