28^th Euro-Global
Neurologists Meeting

Aleksandra Tencheva is a PhD student in Organic chemistry at South-West University Neofit Rilski, Bulgaria. She has been evaluating her PhD thesis under the supervision of Prof. Ivanka Stankova, PhD. Tencheva's research interest is in design of drugs with potentional neuroprotective activity. She has been taken part in young project (MU-23/2018) entitled Newly memantine analogues with potential protective effects for the treatment of dementia of the Alzheimer's type.

Despite of extensive investigations of finding causes for Alzheimer's disease (AD), the etiology of this neurological disorder is rather complicated. Currently, the only drug approved for a treatment for moderate to severe Alzheimer's disease is memantine (1-amino-3, 5-dimethyladamantane). This clinical drug is known as an open-channel, non-competitive N-methyl-D-aspartate (NMDA) receptor inhibitor. Considering the multifactorial nature of AD, the monotherapy concerning one-compound - one-target has not reached the desired effect. Therefore, in the recent years the hybrid-based approach has emerged as a promising therapy for Alzheimer’s disease. Following the multitarget approach, herein, amide-modified memantine with different substituted cinnamic acids were designed in order to investigate their effects in an in vitro AD model. Methodology and Theoretical Orientation: Synthesis: The target memantine amides (Fig. 1) were obtained in moderate yields (40–70%) based on the N-(3-dimethylaminopropyl)- N’-ethylcarbodiimide hydrochloride (EDC) as coupling agent and HOBt as catalyst (SHEEHAN, 1961). Neuroprotective effects of memantine derivatives: APPswe cells injured by copper, which triggers β-amyloid toxicity, were served as an AD model in vitro. The MTS assay was used to examine the protective effects of the memantine derivatives on copper injured APPswe cells. EC50 value was used to evaluate the efficacies for neuroprotection of the memantine hybrids as well as the positive drug memantine hydrochloride. Conclusion and Significance: The results demonstrated that the tested hybrid compounds showed protective effects on improving APPswe cell viability due to copperinduced toxicity. The EC50 ranging from (18.23 ± 1.08) μM to (35.24 ± 1.84) μM

Ishaar Ganesan has his expertise in computational neuroscience, coding, and data analysis. With his group, they developed a new Myoelectric Computer Interface on the basis of the previous, flagship study on the MCI. After more than a year of experience in this field and working on this project, the final product is nearing completion. The foundation for this project is based on the paradigm initially designed by Tomic et al. that effectively utilized a game controlled by the MCI to reduce abnormal coactivation of muscles in stroke survivors [5]. This foundation has allowed creating a device that can play a pivotal role in bringing severe stroke patients around the world an easier, more efficient method of rehabilitation.

Ishaar Ganesan has his expertise in computational neuroscience, coding, and data analysis. With his group, they developed a new Myoelectric Computer Interface on the basis of the previous, flagship study on the MCI. After more than a year of experience in this field and working on this project, the final product is nearing completion. The foundation for this project is based on the paradigm initially designed by Tomic et al. that effectively utilized a game controlled by the MCI to reduce abnormal coactivation of muscles in stroke survivors [5]. This foundation has allowed creating a device that can play a pivotal role in bringing severe stroke patients around the world an easier, more efficient method of rehabilitation.

Lyubka Tancheva is an associated professor at the Institute of Neurobiology, Bulgarian Academy of Sciences and also is working as Weston Professor of Weizmann Institute of Science, Rehovot, Israel. Her research interests are in the field of pharmacological treatment of cognitive disorders with natural and synthetic compounds. She is working on the complex mechanisms of neurodegenerative disorders and the possibilities for their prevention. Tancheva is a co-author of several guidebooks & educational materials for students in Medicine and Pharmacy. She also is supervisor of many Master and PhD students.

Methodology and Theoretical Orientation: Snail extract (SE) is a rich source of biologically active substances with strong anti-inflammatory, antioxidant and immunomodulatory activities. We evaluated SE effects in experimental models of Alzheimer's disease (AD) and Parkinson's disease (PD). Crude mucus was collected from snail Helix aspersa and fresh extract was purified. PD was induced via 6-OHDA injection (10µg /2 µl) in right striatum of male Wistar rats. 6-OHDA-lesioned group received for 13 days fresh snail extract orally (0.5 ml/100 g b.w; 6 days before and 7 days after striatal lesion). Behavioral data and biochemical parameters of oxidative stress were measured in 6-OHDA-lesioned group without treatment as well as in sham-operated (SO) rats. AD was induced via scopolamine treatment (Sco, 2 mg, i.p, 11 days). Snail+Sco treated group received for 16 days SE orally (0.5 ml/100 g b.w; 5 days before, and 11 days simultaneously with Sco). Changes in lipid peroxidation (LPO) and total glutathione levels, as well as the activities of superoxide dismutase, catalase and glutathione peroxidase in the rat brain structures were assayed spectrophotometrically. Findings: The results of behavioral tests showed that in 6-OHDA and Sco groups there were significant motor, memory and biochemical impairment in compared to SO and control groups. The SE treatment had a memory improving effect on demented rats, and memory and motor beneficial effect in PD group. These changes were accompanied by significant decrease in brain LPO and recovery of superoxide dismutase activity, increased significantly both by the 6-OHDA and by Sco treatment. Conclusion and Significance: Snail extract had a beneficial effects on experimental rat model of AD and PD confirmed both behaviorally and biochemically. Acknowledgements: Supported by Grant D01-217/30.11.2018 from Bulgarian Ministry of Education and Science under National Scientific Program "Innovative Low-Toxic Biologically Active Means for Precision Medicine" (BioActiveMed).

Radoslav Chayrov is a researcher in the field of drug design and modification on natural biologically active compounds. He started his scientific work under the supervision of Prof. Ivanka Stankova in South-West University on 2009 as a bachelor student. Two years later in 2011 He completed his master's degree - "Biologically active compounds and drugs". In 2014 he started PhD education and graduated successfully in 2017. The thesis topic is "Synthesis and analysis by HPLC of antiviral drug analogues". In present he is co-author of two patents related to biologically active molecules

Memantine is a NMDA-receptor antagonist that inhibits excessive calcium influx induced by overstimulation of the NMDA receptor. Memantine is approved in the US and the EU for the treatment of patients with moderate to severe dementia of the Alzheimer's type. A series of memantine derivatives incorporating amino-acid residues have been synthesized for the first time and their neuroprotective effects in vitro have been studied. Methodology and Theoretical Orientation: The new amino acids derivatives were synthesized by TBTU as a coupling reagent. Briefly, commercially available tert-butyloxycarbonyl amino acids and memantine underwent a two-step process involving formation of amide bond. Firstly, the N-Boc protected amino acids was transformed to amide group derivatives by the standard condensation reaction. The target compounds were further prepared by removal of the N-Boc protecting group of in the presence of trifluoroacetic acid at 0°C. The final memantine analogues as TFA salt were obtained as a free base using aqueous ammonia Fig. 1. Memantine derivatives protected APPswe cells against copper-induced cytotoxicity. APPswe cells injured by copper, which triggers β-amyloid toxicity, were served as an AD model in vitro. There were two compounds, memantine with aromatic amino acids demonstrating better neuroprotective effects compared with the memantine. Memantine analogues protected PC12 cells against CoCl2-induced cytotoxicity. CoCl2 was used to establish a hypoxic condition for PC12 cells. There were six compounds (memantine with aliphatic and aromatic amino acids) showing approximative neuroprotective effects on PC12 cells against CoCl2-induced toxicity compared to the memantine. Amino acids analogues of memantine inhibited the release of TNF-α and IL-6 caused by lipopolysaccharide (LPS)-stimulated EOC20 cells. The EOC20 cells stimulated by LPS was used to imitate the inflammatory and neurotoxic activation of microglia. ELISA was used to examine the inflammatory cytokine levels in cultural medium released from EOC20 cells simulated by LPS after treated with the 7 compounds. Especially, memantine with aromatic amino acids showed equivalent effects on inhibiting the release of TNF-α and IL-6 on LPS-induced EOC20 cell compared with the positive drug memantine. Conclusion: The rational synthesis of our compounds was based on the fact that some amino esters of certain antivirals (e.g. the antiherpes valacyclovir) are known as prodrugs. Thus, the study of the neuroprotective properties of derivatives of the memantine that contain aromatic and aliphatic amino acids led to compounds which show increased activity, compared to memantine.

Saily Sosa Perez is a member of the Society of Internal Medicine since 1998. She is also a member of the Dementia Section of the Cuban Society of Neurosciences since 1998 and a member of a multidisciplinary medical service for patients with memory disorders, University Hospital Carlos J. Finlay (1994-2010). Her Specialist's thesis is Demographic, clinical and tomographic aspects of Alzheimer's Disease. She is a Postgraduate in epidemiological research and community intervention in demential syndromes. Her master thesis- Clinical Behavior and Diagnostic of Mild Cognitive Impairment. She is currently working as Head of Community Integral Service for Assistance to Memory Disorders (CISAMD) of the General Hospital Ivan Portuondo, Artemisa Province, Cuba (2012-present).

Statement: The aging of the population has resulted in an increase in neurodegenerative disorders. Among them are dementias and specifically Alzheimer's disease (AD) as the highest incidence. Cuba is a developing country with health indicators similar to those of developed countries and with a rapid aging of its total population. It is estimated that by the year 2020, Cuba will become the country in Latin America with the highest proportion of older adults (25% of the population aged 60 and over). That is why the clinic plays an important role in elderly health services in our community. Age, family history (FH), apolipoprotein E (ApoE) genotype, low educational level and female sex are risk factors for AD. Objective: To determine the clinical and demographic characteristics in patients with AD, MCI and people with normal cognition in a Cuban rural population. Methodology and Theoretical Orientation: A transversal descriptive study was carried out including 900 individuals, who were 35 or more years old, evaluated in the CISAMD D from September 2012 to March 2019. All of them were integrally evaluated according to neuropsychologic, genetic, neuroimaging, electroencephalographic and laboratory assays. The individuals were classified in three groups: subjects with normal cognition (288), patients with MCI (270) and with AD probable (342). Findings: In the rural Cuban population studied, MCI and AD have a highly incidence in elderly persons, predominating the senile form of AD. The main risk factors found in patients with MCI and AD were: to be female, have a low education level and familial history and carrying ApoE ε4 genotype. Conclusion and Significance: According to the results of our study the female sex, low education level, FH and to carry the ApoE ε4 genotype are the same risk factors found in urban as rural Cuban populations.