JM-20 protects memory acquisition and consolidation on scopolamine model of cognitive impairment

ABSTRACT

Objective: JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages.

Methods: The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined.

Results: The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions.

Conclusions: The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory deficits associated with AD in humans.

KEYWORDS:

• JM-20
• neuroprotection
• scopolamine
• cognitive impairments
• neurodegeneration

Acknowledgments

The activity leading to the present study has received funding from non-governmental organization MEDICUBA-SPAIN 2010.

Disclosure statement

No potential conflict of interest was reported by the authors.

Highlights

• JM-20 preserves memory acquisition and consolidation impaired by scopolamine in rats

• JM-20 prevents scopolamine-induced spatial and object recognition memory impairments

• The antioxidant, mito-protective and anti-AChE effects appear to mediate memory improvement by JM-20

• JM-20 could be a potential therapeutic candidate for the management of AD.

Additional information

Funding

This work was supported by the non-governmental organization MEDICUBA-SPAIN [2010].

Notes on contributors

Maylin Wong-Guerra

Maylin Wong Guerra. Bachelor's at Biochemistry and Molecular Biology (2013), master's at Pharmacology (2016) from Havana University and PhD student in the Experimental Neuropharmacology Lab of CIDEM where new therapeutic candidates are evaluated to treat some of neurodegenerative diseases. Has experience in Pharmacology, focusing on Neurosciences and behavioral studies, acting on the following subjects: synthetic and natural products, mitochondrial dysfunction, oxidative stress, neuroinflammation, cognitive and motor dysfunction, and animal models of neurodegenerative diseases.

Javier Jiménez-Martin

Javier Jimenez-Martin is a PhD student at the Empson Lab, at the University of Otago, New Zealand. He has a Honours (BSc(Hons)), majoring in Biology, University of Havana, Cuba. During his PhD in the Empson Lab he is studying the effect of cholinergic neurons in motor learning and he has pioneered somatosensory voltage imaging in awake mice. He possesses advanced animal handling and behavioural skills and has a strong scientific track record. He holds the University of Otago Doctoral Scholarship and is the Otago Brain Health Research Centre Roche Scholar in 2019.

Luis Arturo Fonseca-Fonseca

Luis Arturo Fonseca Fonseca. Bachelor's at Biochemistry and Molecular Biology (2013), master's at Pharmacology (2016) from Havana University and PhD student in the Experimental Neuropharmacology Lab of CIDEM where new therapeutic candidates are evaluated to treat some of neurodegenerative diseases. Has experience in cell culture, immunohistochemistry, molecular biology techniques, Pharmacology, focusing on Neurosciences and behavioral studies, acting on the following subjects: synthetic and natural products, mitochondrial dysfunction, oxidative stress, cognitive and motor dysfunction.

Jeney Ramírez-Sánchez

Jeney Ramírez Sánchez. Bachelor's at Biochemistry from Havana University (2010) and master's at Pharmacology from Havana University (2014). Researcher at Drug Research and Development Center (CIDEM, Havana, Cuba). Has experience in Neuropharmacology, focusing on the preclinical testing of candidates for neurodegenerative diseases, with emphasis on ischemic stroke.

Yanay Montano-Peguero

Yanay Montano Peguero has a degree in pharmaceutical sciences. She is currently studying a master's degree in pharmacology. She works in the CIDEM, specifically in the laboratory of Experimental Neuropharmacology where new therapeutic candidates are evaluated to treat neurodegenerative diseases. She has publications related to this topic and has participated in national and international events.

Joao Batista Rocha

Joao Batista Teixeira da Rocha. Bachelor's at Ciências Biológicas from Universidade Federal do Rio Grande do Sul (1986), master's at Biochemistry from Universidade Federal do Rio Grande do Sul (1989) and doctorate at Biochemistry from Universidade Federal do Rio Grande do Sul (1996). Has experience in Pharmacology, focusing on Toxicology, acting on the following subjects: diphenyl diselenide, brain development, ebselen, oxidative stress and undernutrition.

Fernanda D´Avila

Fernanda D'Avila. Bachelor's at Biomedicine from Universidade Franciscana (UFN) (2012), master's at Nanoscience with a focus on the vectorization of drugs for the treatment of pathologies associated with the central nervous system, by the Franciscan University (UFN) (2015). He has experience in the area of Clinical Pathology, Nanosciences, Biochemistry, Toxicology and Enzimology. She is currently a CAPES PhD student in Biological Sciences: Toxicological Biochemistry by the Federal University of Santa Maria (UFSM), developing studies with alternative experimental models for toxicity evaluation of compounds.

Adriano M. de Assis

Adriano Martimbianco de Assis. Bachelor's degree in Physical Education from the Lutheran University of Brazil (2004), Specialization in Health Sciences and Sports Medicine from the Pontifical Catholic University of Rio Grande do Sul (2005) and Masters (2009) and Doctorate (2011) in Biological Sciences: Federal University of Rio Grande do Sul - UFRGS. During the doctorate he undertook a short mission in the laboratory of Prof. Luc Pellerin (Université de Lausanne, Switzerland) in 2011. PNPD in the Post-Graduation in Health Sciences of the Federal University of Health Sciences of Porto Alegre - UFCSPA (2011-12) with emphasis on cellular biology. PNPD (2012-2017) and Associate Professor (2014-present) in the Graduate Program in Biological Sciences: Biochemistry by the Federal University of Rio Grande do Sul - UFRGS, with emphasis on neuroenergetics and neuroprotection. Professor of graduation (2016-2017) in the discipline of Medical Biochemistry I in Medicine - UFRGS. Assistant Professor I (2017-Present) at the Catholic University of Pelotas - UCPEL linked to the Postgraduate Program in Health and Behavior. Visiting Abroad - PVE / CAPES (2018-2019) at the Department of Physiology, Université de Lausanne, Switzerland. Has experience in Biochemistry and Human Physiology.

Diogo Onofre Souza

Diogo Onofre Gomes de Souza. He completed his medical studies in 1971, at the Catholic University of Pelotas. Master´s (1976) and Doctorade (1980) from Universidade Federal de Rio de Janeiro (UFRJ). Post Doutorade (CNPq) at the University of London (1980-1981); Visiting Professor at the Laboratory of Neurobiology (1987-1988), Universidad Autónoma de Madrid; Visiting Professor at the Laboratory of Bioenergetics (1994-1995), Department of Medical Biochemistry, UFRJ; Visiting Scientist (1998), Neurology Service, Veterans Affair Medical Center, CA, USA. He has published more than 450 scientific articles in international journals and has supervised numerous Doctoral Theses, Master's Dissertations and dozens of students of Scientific Initiation. This performance basically involves the area of Neuroscience, working in brain injury mediated by glutamate and neuroprotection exercised by the nucleoside guanosine, addressing basic and clinical aspects of brain diseases. Recently he started to get involved in the area of Science Education, where he supervised several Doctoral Theses and Master's Dissertations. He recently led the creation of a PPG in Science Education at UFRGS, having been its first Coordinator. Currently, he is a reviewer of scientific articles in more than 30 indexed international journals.

Gilberto L. Pardo-Andreu

Gilberto L Pardo Andreu holds a PhD degree in Pharmaceutical Sciences. He is Senior Researcher at the Institute of Pharmaceutical and Foods Sciences of the University of Havana (Cuba). He has more than 100 papers in the field of mitochondrial pharmacology. His researches are focused in the elucidation of the pharmaco-toxicological mechanism of bioactive compounds, emphasizing in their effects on mitochondria. In this sense, several promising neuroprotective, anti-diabetic and anti-cancer molecules that modulate mitochondrial function have been discovered in his lab. He also provides continuing education lectures regarding mitochondrial assessment for drug development at pre and post graduate levels.

Roberto Menéndez-Soto del Valle

Roberto Menendez Soto del Valle is Biochemist, Dr. in Pharmaceutical Sciences who has worked in the pharmacological evaluation of natural products and compounds of synthetic origin. He has extensive experience in biomodels related to lipid metabolism, antioxidant and anti-inflammatory effects, cytoprotective action, on prostatic hyperplasia and memory and learning among others. He has also developed general toxicology studies and pharmacokinetic and metabolism studies. He currently works at the Grupo de Neuroquimica, Cuban Neurosciences Center. He has several publication and presented several poster and has held lectures in national and international events as well as postgraduated studies. Due his long standing career he has received the “Lifetime Achievement Award 2017” for the contribution to all disciplines of Pharmacology in his Country, granted by the Cuban Society of Pharmacogy.

Guillermo Aparicio Lopez

Guillermo Aparicio López is a Doctor in Veterinary Medicine, and Specialist in Pathological Anatomy at Drugs Research and Development Center, Havana, Cuba. He obtained a Master's Degree in Experimental Toxicology and Diplomat in Veterinary Histopathology and Advanced Veterinary Oncology. He has several publications in Preclinical Pharmacological and Toxicological Studies fields on histopathological valuations of natural and synthetic products as well as its combinations in cancer treatments and Diseases of the Central Nervous System, mainly Neurodegenerative illness. He has also presented numerous posters and oral presentations in National and International Events and he has contributed as coauthor in research works awarded and a Prize of Cuban Sciences Academy. He is a member of the Hispanic Organization for Toxicologists (HOT). He is a member of the Scientific Veterinary Council of Cuba and of the Cuban Society of Veterinary Pathology. He is a teacher of Histopathology in Diplomat in Histopathology as part of a Master Course in Toxicology at Food and Pharmacy Institute from Havana University.

Odalys Valdés Martínez

Odalys Valdes Martínez is a specialist in Health Technology focused to Histopathology. She has several publications in pre-clinical studies of potential synthetic natural products for the treatment of the central nervous diseases. In addition, she presented numerous posters at national and international conferences regarding stroke, cancer and neuropathic pain. He also provides continuing education in the processing of tissue samples for histopathological studies.

Nelson Merino García

Nelson Merino García is a Doctor of Veterinary Medicine and Doctor of Science in Veterinary Pathology, retired who provides his services and extensive knowledge in Histopathological diagnosis to many research centers of the BioCubaFarma Business Group (including CENIC, CIDEM, CIGB and CENPALAB). It has numerous national and international scientific publications of Histopathological Studies in the field of preclinical pharmacological research as well as in the Anatomopathological diagnosis of diseases affecting domestic animals. He is an honorary member of the Scientific Veterinary Council of Cuba and of the Cuban Society of Veterinary Pathology. He has been invited to give master lectures at national and international events and is an adjunct professor at the Faculty of Veterinary Medicine of the Agrarian University of Havana, where he teaches Pathological Anatomy. He has been tutor of countless doctoral, master's and undergraduate theses, has been part of courts in these types of theses and in national and international events, evaluator of publications for national scientific journals.

Abel Mondelo-Rodríguez

Abel Mondelo Rodríguez is a chemical engineer with a Masters’ in environmental engineering and holds a diploma in scale-up of chemical processes. He has publications in carbohydrate synthesis, organic synthesis, water and wastewater treatment, environmental monitoring and recently, in pharmacology. He has also presented numerous posters at national and international chemical and environmental conferences regarding carbohydrate synthesis, water and wastewater treatment, environmental monitoring, environmental diagnosis and hazardous wastes. In addition, he is reviewer of the Journal of Hazardous Material of the Elsevier. He also provides practical research regarding experimental chemistry for the faculty of Chemistry, University of Havana.

Alejandro Saúl Padrón-Yaquis

Alejandro Saul Padrón Yaquis is the general director at Drug Research and Development Center of Havana City, Cuba. Ph.D. Pharmaceutical Sciences, Senior Researcher. He has obtained several awards, such as: National Prize of the Cuban National Sciences Academy; Annual National Awards of Health conferred by Cuban Ministry of Health. His research experience is related to pharmacokinetic and bioequivalence studies with several results published in important journals. He has developed an intense and productive international collaboration, participating and directing several international projects.

Yanier Nuñez-Figueredo

Yanier Nuñez Figueredo is the head of the Experimental Neuropharmacology Laboratory at CIDEM of Havana City, Cuba. Ph.D. Pharmaceutical Sciences, Senior Researcher. He has obtained several awards, such as: National Prize of the Cuban National Sciences Academy; Annual National Awards of Health conferred by Cuban Ministry of Health and Prize of Pharmacolo-gy, conferred by Cuban Society of Pharmacology. His research experience is related to the evaluation of neuroprotective, anti-oxidant and mitoprotective activities of natural and synthetic products, and was published in important journals. He has developed an intense and productive international collaboration, participating and directing several international projects.