Background: Alzheimer's disease is a progressive neurodegenerative process with multifactorial characteristics. This disease follows the natural aging process, affecting mainly people over 65 years. Pharmacotherapeutic treatment currently combats symptoms related to cognitive function. Several targets have begun to attract the interest of the scientific community to develop new drug candidates which have better pharmacokinetic and lower toxicity parameters.
Objective: The present study aims to design new candidates for acetylcholinesterase/β-secretase (AChE/BACE1) multitarget inhibitor drugs.
Methods: 17 natural products were selected from the literature with anticholinesterase activity and 1 synthetic molecule with inhibitory activity for BACE1. Subsequently, the molecular docking study was performed, followed by the derivation of the pharmacophoric pattern and prediction of pharmacokinetic and toxicological properties. Finally, the hybrid prototype was designed.
Results: All selected molecules showed interactions with their respective target enzymes. Derivation of the pharmacophoric pattern from molecules that interacted with the AChE enzyme resulted in 3 pharmacophoric regions: an aromatic ring, an electron-acceptor region and a hydrophobic region. The molecules showed good pharmacokinetic and toxicological results, showing no warnings of mutagenicity and/or carcinogenicity. After the hybridization process, three hybrid molecules were obtained, which showed inhibitory activity for both targets.
Conclusion: It is concluded that research in the field of medicinal chemistry is advancing towards the discovery of new drug candidates that bring a better quality of life to patients with AD.
Background: A simultaneous administration of an acetylcholinesterase (AChE) inhibitor and a NSAID as a drug cocktail has been documented to exhibit significantly protective effects in AD patients. But it suffers from poor patent compliance, pharmacodynamics and pharmacokinetic issues.
Objective: The present study is aimed to design and synthesize a hybrid molecule capable of exhibiting both AChE inhibition and anti-inflammatory activities for de-accelerating the progression of AD. The synthesized molecules will be evaluated for in vitro and in vivo models.
Methods: The present study involves the coupling of ibuprofen or naproxen to varied disubstituted amines (AChE inhibitor pharmacophore) through benzimidazole to develop two series of compounds i.e. IB01-IB05 and NP01-NP05. The synthesized compounds were characterized using FTIR, 1H-NMR, 13C-NMR and MS. All compounds were evaluated for in vitro AChE inhibitory and COX inhibitory activities. The most active compound was taken for in vivo evaluation.
Results: Compounds of series IB01-IB05 are found more potent as compared to NP01-NP05. The maximally potent compound IB04 in in vitro evaluation is selected for in vivo evaluation of memory restoration activity using scopolamine-induced amnesia model in mice. It significantly reverses the scopolamine-induced changes (i.e., escape latency time, mean time spent in target quadrant, brain AChE activity and oxidative stress) in a dose-dependent manner. IB04 at 8 mg/kg is significantly effective in lowering AD manifestation in comparison to donepezil.
Conclusion: The findings indicate that Benzimidazole hybrids utilizing ibuprofen and pyrrolidine moiety may prove a useful template for the development of new chemical moieties against AD with multiple potencies.
Background: Ellagic acid (EA) has various pharmacological effects such as antiinflammatory and anti-oxidant effects.
Objective: This study aimed to investigate the effects of EA on learning and memory dysfunction as well as oxidative stress in scopolamine-induced amnesic rats.
Methods: The studied rats were treated according to the following protocol: Control (group 1) and scopolamine (group 2) groups received saline (intraperitoneal injection (i.p.)) while the treatment groups (group 3-5) were given EA (25, 50, and 100 mg/kg, i.p.) for 3 weeks. Thereafter, their behavioral performance was evaluated using Morris water maze (MWM) and passive avoidance (PA) tasks. Notably, scopolamine was injected (into groups II-V at a dose of 2 mg/kg, i.p.) before conducting the tasks. Finally, the oxidative stress indicators in the brain were measured.
Results: EA reduced the escape latencies and distances during the learning phase of MWM. The results of probe trials also indicated that EA improved memory retrieval and helped animals recall the platform. Moreover, EA increased delay and light time, while decreasing the frequency of entries to the dark area of PA. In the EA-treated groups, the level of malondialdehyde was decreased, while the levels of total thiol groups, superoxide dismutase, and catalase were increased.
Conclusion: EA prevented the negative effects of scopolamine on learning and memory which is probably mediated via modulating oxidative stress. Hence, EA could be considered as a potential alternative therapy for dementia.
Background: Escitalopram, a selective serotonin reuptake inhibitor (SSRI), acts by increasing the serotonin level in the brain and is used widely for the management of depression and anxiety disorders. However, the poor dissolution rate of escitalopram due to less water solubility is a consequential problem confronting the pharmaceutical industry in developing pharmaceutical dosage forms for oral delivery systems.
Objective: The present work aims to deliver a novel formulation for improving the dissolution profile and, thus, the bioavailability of escitalopram.
Methods: Fast Dissolving Tablets (FDT) are expected to enable quick drug release, which will improve the drug's dissolving profile, allowing for the initial increase in plasma concentration mandatory in an acute depression attack. The use of co-processed excipients in tablets has been shown to increase the compressibility and disintegration properties of the tablets, resulting in improved in-vitro drug release and bioavailability. As co-processed excipients, a mixture of banana powder (a natural super disintegrant with nutritional value) and microcrystalline cellulose (a highly compressible substance with good wicking and absorption capacity) was used.
Results: The tablets were made using a response surface, randomised central composite design, and a direct compression technique. The manufactured tablets were found to be released more than 95% of the drug within 10 minutes and showed an improved drug release profile than the available marketed formulation.
Conclusion: After confirming in-vivo potential, the fast release formulation exhibited impressive in-vitro findings and may prove to be a boon in treating acute depression attacks.
Background: Neuroinflammation is a key component in the etiopathogenesis of neurological diseases and brain aging. This process involves the brain immune system that modulates synaptic functions and protects neurons from infection or damage. Hence, the knowledge of neuroinflammation related pathways and modulation by drugs or natural compounds is functional to developing therapeutic strategies aimed at preserving, maintaining and restoring brain health.
Objective: This review article summarizes the basics of neuroinflammation and related signaling pathways, the success of the dietary intervention in clinical practice and the possible development of RNA-based strategies for treating neurological diseases.
Methods: Pubmed search from 2012 to 2022 with the keywords neuroinflammation and molecular mechanisms in combination with diet, miRNA and non-coding RNA.
Results: Glial cells-play a crucial role in neuroinflammation, but several pathways can be activated in response to different inflammatory stimuli, inducing cell death by apoptosis, pyroptosis or necroptosis. The dietary intervention has immunomodulatory effects and could limit the inflammatory process induced by microglia and astrocytes. Thus by inhibiting neuroinflammation and improving the symptoms of a variety of neurological diseases, diet exerts pleiotropic neuroprotective effects independently from the spectrum of pathophysiological mechanisms underlying the specific disorder. Furthermore, data from animal models revealed that altered expression of specific noncoding RNAs, in particular microRNAs, contributes to neuroinflammatory diseases; consequently, RNA-based strategies may be promising to alleviate the consequences of neuroinflammation.
Conclusion: Further studies are needed to identify the molecular pathways and the new pharmacological targets in neuroinflammation to lay the basis for more effective and selective therapies to be applied, in parallel to dietary intervention, in the treatment of neuroinflammation-based diseases.
Introduction: Ischemic stroke remains the leading cause of death worldwide and is the primary cause of disability globally. Numerous studies have shown that plant-origin medicines are promising and can influence the treatment of neurological disorders. Phyllanthus embilica L. (P. emblica or Amla) is one of the herbal plants whose medicinal properties are widely studied. The objective of the present study is to determine the neuroprotective effects of an aqueous extract of the fruit of P. emblica (hereinafter referred to as just P. emblica) on cerebral ischemia-reperfusion injury and explore if it can regulate BDNF/PI3K pathway to modulate glutathione for mitoprotection and neuroprotection.
Methods: In vivo studies were conducted on male Sprague Dawley rats, where rats were prophylactically administered 100 mg/kg P. emblica for 30 days. In the treatment group, rats were given 100 mg/kg P. emblica, 1 h post middle cerebral artery occlusion (MCAo). Rats were evaluated for neuro deficit and motor function tests. Brains were further harvested for infarct size evaluation, biochemical analysis, protein expression studies, and mitochondrial studies.
Results: Prophylaxis and treatment with P. emblica demonstrated significant improvement in functional outcome with a reduction in infarct size. Normalization of glutathione, nitrite, and malondialdehyde levels was also observed. Improvement in mitochondrial complex I and IV activities was also reported. Expressions of BDNF, PI3K, SDF1 and VEGF increased while that of ROCK2 decreased following P. emblica administration.
Conclusion: P. emblica regulates BDNF/PI3K pathway to modulate glutathione in ischemic stroke to confer mitoprotection and neuroprotection.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：