Central nervous system agents in medicinal chemistry最新文献

Background: Parkinsonism is a neurodegenerative disorder with a heavy disease burden, despite the discovery and application of drugs. Current research is beginning to suggest the possible crucial roles of micronutrients such as pyridoxal phosphate in the prevention or management of neurodegenerative disorders.

Objective: We investigated the possible protective effects of supplemental pyridoxal phosphate in Chlorpromazine (CPZ)-induced Parkinsonism-like changes in mice.

Methods: Mice were assigned to eight groups of 30 mice each. Groups included Vehicle control (fed standard diet (SD), and administered intraperitoneal {ip} injection of saline and saline per orem), levodopa-carbidopa (LD) group (SD, saline ip and LD per orem), two groups fed pyridoxal phosphate-supplemented diet (at 100 and 200 mg/kg of feed), and administered saline both ip and orally, CPZ group (SD, CPZ ip and saline per orem), CPZ/LD group (SD, CPZ ip and LD per orem) and finally two groups fed pyridoxal phosphate -supplemented diet (at 100 and 200 mg/kg of feed) and administered CPZ ip plus saline per orem. Treatments were administered daily for a period of 21 days to allow for the induction of Parkinsonism features. Body weight and food intake were measured weekly while neurobehavioural and biochemical tests were assessed at the end of the experimental period.

Results: Pyridoxal phosphate supplementation was associated with a reduction in CPZ-induced suppression of open-field horizontal locomotion and rearing; and a significant increase in grooming activity. Administration of pyridoxal phosphate-supplemented diet was also associated with improvements in working-memory in CPZ-treated mice; and there was reduction in the index of anxiety and catalepsy score.

Conclusion: Pyridoxal phosphate supplementation was associated with significant benefits in CPZ-induced Parkinsonism-like changes in mice.

Background: Chronic stress elevates the cortisol beyond normal levels, which affects cognition including learning & memory. This injurious effect is primarily mediated via over excitation of metabotropic glucocorticoid receptors (mGR).

Methods: The present study was aimed to appraise the neuroprotective effects of naturally occurring molecule β-1,3-glucan by interfering with stress-cortisol-mGR axis. Our data of virtual screening (in silico) exhibited the promising interactions of β-glucan with the mGR. Therefore, the study was extended to evaluate its efficacy (2.5, 5 and 10 mg/kg/ i.p) in an animal model of chronic unpredictable mild stress (CUMS, 28 days) induced memory impairment.

Results: Results of the current study revealed the β-glucan provided dose dependent protection against deleterious effects of stress on learning and memory associated parameters observed in Morris water maze (MWM) task. At higher tested doses, it has also significantly antagonized the stress induced weight loss and corticosterone elevation.

Background: Citrus limon a small evergreen plant belongs to the family Rutaceae. These species are extensively cultivated throughout the world because of their multiple health benefits for humans and their applications in the pharmaceutical and food industries. Various studies were conducted using their plant parts (fruits, flowers, peels, leaves, blossoms) but the studies on peel extracts are very limited. However, the anticonvulsant activity of peels has not been studied yet.

Objective: The main goal of this study is to appraise the anticonvulsant effect stimulated by the antioxidant property of hydroalcoholic extracts of Citrus limon (HAECL) peels in various animal models.

Methods: The anticonvulsant and in vivo antioxidant activity of HAECL peels was observed by Maximal electric shock (MES) model, pentylenetetrazole (PTZ) induced clonic convulsion model and PTZ induced kindling test. The extract was administered to test groups at doses of 200, 400 and 600 mg/kg. orally in PTZ and MES methods. The highest dose of extract was given to the test grouped animals in case of a kindling test. After completion of the time period of kindling, the brains of all grouped animals were isolated and subjected to analyse oxidative stress parameters such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) biochemically to investigate the antioxidant profile of the plant.

Results: HAECL peels at doses of 400 and 600 mg/kg significantly (p<0.01) delayed the onset, decreased the duration of myoclonic spasm in PTZ induced seizure model and also significantly (p<0.01) decreased the duration of hind limb tonic extension (HLTE) as well as significantly (p<0.05) increased the postictal depression (PID) in MES model compared to control. In the PTZinduced kindling model, the malondialdehyde (MDA) level was elevated with a diminished level of SOD, CAT, GSH compared to the control group but pretreatment with HAECL at the highest dose reduced the MDA level and refined SOD, CAT and GSH status effectively.

Conclusion: From the above investigation, it was concluded that HAECL could produce significant anticonvulsant activity and also attenuate oxidative stress-induced during a seizure.

Background: A correlation between cognitive dysfunctions and brain insulin resistance has been established by several clinical and experimental studies. Consistent data support that people diagnosed with brain insulin resistance, resulted from diabetes, have shown an increased risk of presenting cognitive dysfunctions, clinical signs of dementia and depression, then speculating a role of dysregulations related to insulin signalling in these diseases. Furthermore, it is currently discussed that Ca2+ signalling, and its dysregulations, may be a factor which could correlate with brain insulin resistance and cognitive dysfunctions.

Objective: Following this, revealing this interplay between these diseases may provide novel insights into the pathogenesis of such diseases.

Methods: Publications covering topics such as Ca2+ signalling, diabetes, depression and dementia (alone or combined) were collected by searching PubMed and EMBASE.

Results: The controlling of both neurotransmitters/hormones release and neuronal death could be achieved through modulating Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling).

Conclusion: Taking into account our previous reports on Ca2+/cAMP signalling, and considering a limited discussion in the literature on the role of Ca2+/cAMP signalling in the link between cognitive dysfunctions and brain insulin resistance, this article has comprehensively discussed the role of these signalling pathways in this link (between cognitive dysfunctions and brain insulin resistance).

Background: Benzimidazole (albendazole), imidazothiazole (levamisole) and imidazole (euconazole) are used in chemotherapy of helminthosis and mycosis respectively, with central nervous system (CNS) side effects. But only a limited number of azole groups are used clinically in the treatment of CNS diseases, which are on increase and could not be cured permanently. Due to increased incidence of more challenging new CNS diseases, there is a need for the synthesis of more potent CNS drugs.

Methods: Hence, literature studies were carried out for the identification of common pathways for the synthesis of the three groups of compounds, their CNS properties and the possibility of modifying them to potent CNS drugs.

Results: Findings have shown that gloxal with formaldehyde in the presence of ammonia can be converted into imidazole, imidazothiazole and benzimidazole via distillation, condensation, alkylation, acylation, oxidation, cyclization, sulphation and amidation. However, agents such as phosphorus pentoxide, ethanolic potassium hydroxide, sodium hypochlorite, sodium hexafluroaluminate, aniline, calcium acetate, calcium benzoate, sodium hydroxide, aromatic aldehydes, bromoketones, alpha dicarbonyl compounds among others are used as reagents. The furan ring(s) may have a strong capability of penetrating CNS for the treatment of neurological disorders. The products from the three groups have agonistic, antagonistic, mixed agonistic and mixed antagonistic depressant and stimulant activities due to the presence of heteroatoms such as nitrogen, oxygen and sulphur. Imidazole may be the most potent with best characteristics of CNS penetrability and activity followed by imidazothiazole and benzimidazole.

Conclusion: Azole group is common to all the three classes and may be responsible for some of their CNS effects. The resultant compounds could act via all neurotransmitters, voltage and ligand-gated ion channels and may be chiral.