Current Small Molecule-Based Medicinal Chemistry Approaches for Neurodegeneration Therapeutics.

Neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS) possess multifactorial aetiologies. In recent years, our understanding of the biochemical and molecular pathways across NDDs has increased, however, new advances in small molecule-based therapeutic strategies targeting NDDs are obscure and scarce. Moreover, NDDs have been studied for more than five decades, however, there is a paucity of drugs that can treat NDDs. Further, the highly lipoidal blood-brain barrier (BBB) limits the uptake of many therapeutic molecules into the brain and is a complicating factor in the development of new agents to treat neurodegeneration. Considering the highly complex nature of NDDs, the association of multiple risk factors, and the challenges to overcome the BBB junction, medicinal chemists have developed small organic molecule-based novel approaches to target NDDs over the last few decades, such as designing lipophilic molecules and applying prodrug strategies. Attempts have been made to utilize a multitarget approach to modulate different biochemical molecular pathways involved in NDDs, in addition to, medicinal chemists making better decisions in identifying optimized drug candidates for the central nervous system (CNS) by using web-based computational tools. To increase the clinical success of these drug candidates, an in vitro assay modeling the BBB has been utilized by medicinal chemists in the pre-clinical phase as a further screening measure of small organic molecules. Herein, we examine some of the intriguing strategies taken by medicinal chemists to design small organic molecules to combat NDDs, with the intention of increasing our awareness of neurodegenerative therapeutics.

Restless Legs Syndrome/Willis-Ekbom Disease in Multiple Sclerosis Patients with Spinal Cord Lesions.

INTRODUCTION: Spinal cord lesions in Multiple Sclerosis (MS) patients are associated with a higher risk of restless legs syndrome (RLS). In this study, we investigated the prevalence of RLS, sleep quality, presence and severity of depression, and the relationship of these parameters with cervical cord lesions in patients with RRMS. METHODS: This study was conducted in the outpatient multiple sclerosis clinic of Marmara University Hospital between October 2013 - February 2014, including 93 patients with the diagnosis of MS. After signing informed consent, demographic data, comorbidities and actual medication of the patients were collected. All patients completed the surveys including Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS) and Beck Depression Inventory (BDI). Prevalence of HBS, sleep quality and depression severity were compared between those with and without cervical cord lesions. Furthermore, the relationship between RLS and sleep quality, depression and expanded disability status scale (EDSS) was assessed. RESULTS: From overall patients, 72% were women (n=67) and 28% (n=26) were men. From all subjects, 32% (n=30) fulfilled IRLSSG diagnostic criteria. Fifty-seven percent of the patients (n=53) had pathological spinal cord lesions. Patients with RLS had significantly higher prevalence of pathological spinal cord lesions compared to patients without RLS (p=0.04). Sleep quality was found to be poor in both patients with cervical cord lesions and patients with RLS and this was statistically significant (p=0.031, p=0.0001). CONCLUSIONS: In summary, the possibility of RLS development in RRMS patients increases with the presence of lesions in spinal cord. Sleep quality was found to be poor in both patients with cervical cord lesions and patients with RLS. As RLS is a potentially treatable condition, increased awareness of diagnosis of RLS in MS patients may be important for early treatment and improve the comfort of the patient.

Antidepressant effect of Gentiana olivieri Griseb. in male rats exposed to chronic mild stress.

Background: The flowering parts of Gentiana olivieri, known as 'Afat' in the southeastern Anatolia region of Turkey, are used as a tonic, an appetizer, and for the treatment of several mental disorders, including depression. The purpose of this study is to investigate the antidepressant effect of G. olivieri ethanol extract (GOEE) in a chronic mild stress-induced rat model, which was used to mimic a depressive state in humans, and to compare the effect with that of imipramine.Methods: Male Sprague-Dawley rats were randomly divided into six groups: control, stress, treated with imipramine (positive control) and treated with GOEE at three different (200, 500, 1000 mg/kg) doses groups. The rats in all groups, except the control group, were exposed to chronic mild stress. At the end of the 3-week experimental period, biochemical and behavioral parameters were examined.Results: The results showed that treatment with GOEE or imipramine significantly improved rats' sucrose consumption which was diminished by chronic mild stress, restored serum levels of corticosterone and proinflammatory cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), prevented the increase of liver index of rats. Moreover, in the hippocampus tissue, decreased serotonin and noradrenaline levels were significantly increased by treatment with GOEE or imipramine, and antioxidant parameters (thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), and glutathione (GSH)) were significantly improved by treatment with GOEE though not with imipramine.Conclusion: The data demonstrate that G. olivieri may exert its antidepressant activity by improving monoaminergic system disorders, and by favorably affecting the antioxidant, inflammatory and the endocrine mechanisms.