Current Research in Pharmacology and Drug Discovery最新文献

Background

Psychosocial stress, a common feature in modern societies, impairs cognitive functions. It is suggested that stress hormones and elevated excitatory amino acids during stress are responsible for stress-induced cognitive deficits. Reduced brain-derived neurotrophic factor (BDNF) levels, increased oxidative stress, and alteration of synaptic plasticity biomarkers are also possible contributors to the negative impact of stress on learning and memory. Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor and the first oral therapy for the treatment of erectile dysfunction. It has been shown that sildenafil improves learning and memory and possesses antioxidant properties. We hypothesized that administering sildenafil to stressed rats prevents the cognitive deficit induced by chronic psychosocial stress.

Methods

Psychosocial stress was generated using the intruder model. Sildenafil 3 mg/kg/day was administered intraperitoneally to animals. Behavioral studies were conducted to test spatial learning and memory using the radial arm water maze. Then, the hippocampal BDNF level and several antioxidant markers were assessed.

Results

This study revealed that chronic psychosocial stress impaired short-term but not long-term memory. The administration of sildenafil prevented this short-term memory impairment. Chronic psychosocial stress markedly reduced the level of hippocampal BDNF (P˂0.05), and this reduction in BDNF was normalized by sildenafil treatment. In addition, neither chronic psychosocial stress nor sildenafil significantly altered the activity of measured oxidative parameters (P > 0.05).

Conclusion

Chronic psychosocial stress induces short-term memory impairment. The administration of sildenafil citrate prevented this impairment, possibly by normalizing the level of BDNF.

Purpose

In neonatal intensive care units, applying sucrose solution for analgesia is now a routine treatment for mild procedural pain. Studies of animal and human infants provide clear evidence of benefits in the short term, but few studies have investigated the long term benefits. Thus, we determined whether sucrose could ameliorate painful stimulation during infancy in Sprague–Dawley rats and also explored the long-term effects of repeated sucrose administration during infancy. Female and male rats were included to investigate sex-related differences.

Methods

Rat pups were stimulated either with painful or tactile stimuli for the first 14 days of their lives. Pups were pretreated either with sucrose or not treated before stimulation. Behavioral tests were conducted during adolescence and adulthood. Hotplate, rotarod, open field, elevated plus maze, and radial arm water maze tests were employed to assess the behavioral consequences of early life manipulations and treatments.

Results

Painful stimulation during infancy increased the sensitivity to pain later in life, and sucrose did not remedy this effect. Motility, coordination, anxiety, and cognition tests in adulthood obtained mixed results. Pain during infancy appeared to increase anxiety during adulthood. Learning and memory in adulthood were affected by pain during infancy, and sucrose had a negative effect even in the absence of pain. No sex-related differences were observed in any of the behavioral tests by employing this model of neonatal pain.

Conclusion

Painful stimulation during infancy resulted in deficiencies in some behavioral tests later in life. Sucrose pretreatment did not mitigate these shortcomings and it actually resulted in negative outcomes.

Direct Oral Anticoagulants (DOACs) have revolutionized the treatment of thromboembolic disorders, offering targeted, effective, and safer alternatives to traditional anticoagulants like heparins and vitamin K antagonists (VKAs). Despite their benefits, DOACs have drawbacks, including an increased risk of gastrointestinal bleeding and unsuitability for patients with mechanical heart valves. Recent research has highlighted Factor XI (FXI) as a promising anticoagulation target due to its significant role in pathological thrombosis and minor involvement in normal hemostasis. Abelacimab, an antibody that inhibits FXI, has shown potential in transforming anticoagulation therapy by sparing hemostasis. This review provides a comprehensive analysis of abelacimab, examining its clinical pharmacology and its pharmacokinetic and pharmacodynamic properties. It scrutinizes abelacimab's safety profile and key monitoring parameters. The current evidence supporting its use and potential future research strengthening its position in anticoagulant therapy is also discussed. The objective is to enhance understanding and contribute to discussions around developing safer anticoagulants, particularly for patients at risk for thrombosis.

Recognized as a common microvascular complication of diabetes mellitus (DM), diabetic nephropathy (DN) is the principal cause of chronic end-stage renal disease (ESRD). Patients with diabetes have an approximately 25% risk of developing progressive renal disease. The underlying principles of DN control targets the dual outcomes of blood glucose regulation through sodium glucose cotransporter 2 (SGLT 2) blockade and hypertension management through renin-angiotensin-aldosterone inhibition. However, these treatments are ineffective in halting disease progression to kidney failure and cardiovascular comorbidities. Recently, the dysregulation of subcellular signaling pathways has been increasingly implicated in DN pathogenesis. Natural compounds are emerging as effective and side-effect-free therapeutic agents that target intracellular pathways. This narrative review synthesizes recent insights into the dysregulation of maintenance pathways in DN, drawing from animal and human studies. To compile this review, articles reporting DN signaling pathways and their treatment with natural flavonoids were collected from PubMed, Cochrane Library Web of Science, Google Scholar and EMBASE databases since 2000. As therapeutic interventions are frequently based on the results of clinical trials, a brief analysis of data from current phase II and III clinical trials on DN is discussed.

Plasmodium infection is a health challenge. Although, antiplasmodial drugs kill the parasites, information on the effects of infection and drugs on the expression of some genes is limited.

Malaria was induced in two different studies using NK65 (chloroquine-susceptible, study 1), and ANKA (chloroquine-resistant, study 2) strains of Plasmodium berghei in 30 male Swiss mice (n = 5) in each study. Mice orally received 10 mL/kg distilled water, (infected control), Mefloquine (MF) (10 mg/kg), MF and Curcumin (CM) (25 mg/kg), MF and CM (50 mg/kg), CM (25 mg/kg) and CM (50 mg/kg). Five mice (un-infected) were used as the control. After treatment, total Ribonucleic acid (RNA) was isolated from liver and erythrocytes while Deoxyribonucleic acid (DNA)-free RNA were converted to cDNA. Polymerase Chain Reaction (PCR) amplification was performed and relative expressions of FIKK12, AQP3, P38 MAPK, NADH oxidoreductase, and cytochrome oxidase expressions were determined. Markers of glycolysis, toxicity and antioxidants were determined using ELISA assays. While the expression of FIKK12 was blunted by MF in the susceptible study, co-treatment with curcumin (25 mg/kg) yielded the same results in the chloroquine-resistant study. Similar results were obtained on AQP3 in both studies. Curcumin decreased P38 MAPK in both studies. Plasmodium infection decreased NADH oxidoreductase and cytochrome oxidase but mefloquine-curcumin restored the expression of these genes. While glycolysis and toxicity were inhibited, antioxidant systems improved in the treated groups. Curcumin is needed for effective therapeutic efficacy and prevention of toxicity. Plasmodium infection and treatment modulate the expressions of some genes in the host. Curcumin combination with mefloquine modulates the expression of some genes in the host.

Alteration of mitochondrial metabolism by various mutations or toxins leads to various neurological conditions. Age-related changes in energy metabolism could also play the role of a trigger for neurodegenerative disorders. Nonetheless, it is not clear if restoration of ATP production or supplementation of brain cells with substrates for energy production could be neuroprotective. Using primary neurons and astrocytes, and neurons with familial forms of neurodegenerative disorders we studied whether various substrates of energy metabolism could improve mitochondrial metabolism and stimulate ATP production, and whether increased ATP levels could protect cells against glutamate excitotoxicity and neurodegeneration. We found that supplementation of neurons with several substrates, or combination thereof, for the TCA cycle and cellular respiration, and oxidative phosphorylation resulted in an increase in mitochondrial NADH level and in mitochondrial membrane potential and led to an increased level of ATP in neurons and astrocytes. Subsequently, these cells were protected against energy deprivation during ischemia or glutamate excitotoxicity. Provision of substrates for energy metabolism to cells with familial forms of Parkinson's disease also prevented triggering of cell death. Thus, restoration of energy metabolism and increase of ATP production can play neuroprotective role in neurodegeneration. A combination of a succinate salt of choline and nicotinamide provided the best results.