Luis Arturo Fonseca-Fonseca

Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear

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Yanier Núñez-Figueredo

Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear

Jeney Ramírez-Sánchez

Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear

Maylin Wong-Guerra

Universidad de Santiago de Chile

Gilberto L. Pardo‐Andreu

University of Havana

Diogo O. Souza

Universidade Federal do Rio Grande do Sul

Yanay Montano-Peguero

Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear

Estael Ochoa

University of Havana

Víctor Diógenes Amaral da Silva

Universidade Federal da Bahia

Adriano Martimbianco de Assis

Universidade Católica de Pelotas

Alejandro Saúl Padrón-Yaquis

Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear

Cooperative Institutions

Centro de Investigación y Desarrollo de medicamentos

Centro de Aplicaciones Tecnológicas y Desarrollo Nuclear

Universidade Católica de Pelotas

Universidade Federal da Bahia

University of Havana

Centro de Investigación y Desarrollo

Centre d'Innovació i Desenvolupament Empresarial

Centro de Información y Desarrollo de la Mujer

Universidade Federal de Santa Maria

Universidade Federal do Rio Grande do Sul

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Corrigendum to “JM-20 treatment prevents neuronal damage and memory impairment induced by aluminum chloride in rats” [Neurotoxicology 87 (2021) 70–85]

NeuroToxicology (2023)

Maylin Wong-Guerra Yanay Montano-Peguero Jeney Ramírez-Sánchez Javier Jiménez-Martín Luis Arturo Fonseca-Fonseca

Memory Impairment

Neuronal damage

10.1016/j.neuro.2023.09.003

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Effect of JM-20 on Age-related cognitive impairment in mice

Research Square (Research Square) (2024)

Maylin Wong-Guerra Yanay Montano-Peguero Jeney Ramírez-Sánchez Enrique García Alfonso Daniela Hernández-Enseñat

Abstract The decline in cognitive function associated with aging significantly impacts the well-being of elderly individuals and their families. This decline is a major recognized risk factor for neurodegenerative diseases, notably Alzheimer's disease. Animal models of aging provide a platform for evaluating drugs concerning aspects like memory and oxidative stress. JM-20 has demonstrated protective effects on short-term memory acquisition and consolidation, along with antioxidant properties and modulation of Acetylcholinesterase activity. This study assesses the potential protective JM-20 against cognitive decline and age-related memory loss. For the study, aged mice exhibiting aging-associated damage were initially selected. Experimental groups were then formed, and the effect of 8 mg/kg of JM-20 was evaluated for 40 days on aging-related behavior, such as spatial memory, novelty recognition memory, ambulatory activity, and anxiety. Subsequently, animals were sacrificed, and the hippocampal region was extracted for redox studies and to assess acetylcholinesterase activity. Results indicated that JM-20 at 8 mg/kg reversed damage to spatial working and reference memory, exhibiting performance comparable to untreated young adult animals. Furthermore, JM-20 preserved the enzymatic activity of superoxide dismutase, catalase, and total sulfhydryl levels in age-related cognitive impairment in mice, indicating a potent protective effect against oxidative events at the brain level. However, only young, healthy animals showed decreased acetylcholinesterase enzyme activity. These findings provide preclinical pharmacological evidence supporting the neuroprotective activity of JM-20, positioning it as a promising therapeutic candidate for treating memory disorders associated with aging.

Memory Impairment

Cognitive Decline

10.21203/rs.3.rs-4863448/v1

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JM-20 administration to animals with lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine, partially reverses motor damage and oxidative stress

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Luis Arturo Fonseca-Fonseca Laura Reina Taño Portuondo Jeney Ramírez-Sánchez Nancy Pavón Fuentes Abel Mondelo Rodríguez

Abstract Previous studies have shown that JM-20, a new chemical hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. Also, we demonstrated that JM-20 blocks the formation of toxic alpha-synuclein aggregated species and aminochrome cytotoxicity. The present study sought to determine the neuroprotective property of JM-20 in animals with a partial lesion of the nigrostriatal dopamine pathway induced by 6-hydroxydopamine (6-OHDA). For in vivo studies, adult male Wistar rats were lesioned in the right substantia nigra pars compacta (SNpc) with 6-OHDA administration. Fifteen days after surgery, the animals asymmetry levels were assessed. Those with asymmetry values higher than 50% were divided into two groups: animals that did not receive any treatment and those that were administered with JM-20 (40 mg/kg, intragastric via gavage) for 27 days. Every seven days, the asymmetry values of the animals were analyzed until day 42 after the surgery. At the end of the experiment, the animals were euthanized and the SNpc and striatum were taken out for the analysis of oxidative stress. Our results reveal a behavioral function progressively recovered in the JM-20-treated animals, diminishing the percentage of motor asymmetry. Also, it improves some oxidative stress markers in the SNpc and the striatum of these animals. Our study provides the preclinical evidence to support the long-term neuroprotective potential of JM-20 in 6-OHDA hemiparkinson rat model, pointing out to its possible use as a disease-modifying agent in PD.

Pars compacta

Hydroxydopamine

Oxidopamine

Nigrostriatal pathway

MPTP

Neurotoxicity

Rotenone

10.1101/2024.07.30.605870

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Antioxidant and neuroprotective effects of gossypitrin, a flavonoid from Talipariti elatum, against chemical hypoxia-induced PC12 cell death

Journal of Pharmacy & Pharmacognosy Research (2018)

María A. Bécquer-Viart José González-Yaque Luis Arturo Fonseca-Fonseca Yanier Núñez-Figueredo Gilberto L. Pardo‐Andreu

Context: Some flavonoids have been described as neuroprotectors. Gossypitrin (Gos) is a natural occurring flavonoid and the main bioactive substance from the flowers of Talipariti elatum Sw. (Majagua azul), traditionally used in Cuba as expectorant and antiasthmatic. Only few reports have documented its antioxidant properties. Aims: To evaluate the antioxidant and cytoprotective effects of Gos against cyanide-induced oxidative stress and cell death in PC12 cells. Methods: Gos effects on DPPH/ ABTS radical scavenging, ferric reducing power and lipid peroxidation were examined. The ischemia/reperfusion neuronal damage was produced by exposing PC12 cells to KCN in glucose-free medium. Gos was added to the incubation medium 30 min before chemical hypoxia induction. The neuroprotective potential of Gos was assessed by measuring cell viability by the MTT assay, the antioxidant enzymes SOD and CAT, and GSH and lipid peroxidation levels. Rutin (Rut), the well-known antioxidant, was used as a reference compound. Results: Gos showed a potent intrinsic antioxidant capacity evidenced by low IC50 and EC50 values for DPPH/ABTS/malondialdehyde and ferric reducing power, respectively. Pre-treatment of PC12 cells with Gos, significantly increased their survival against KCN, restored the levels of GSH and the SOD and CAT enzymes activities, as well as reduced the level of lipid peroxidation. Its antioxidant effects were higher than those elicited by Rut. Conclusions: The results show for the first time the neuroprotective potential of Gos against hypoxic cell damage, probably associated to its antioxidant effects.

ABTS

Malondialdehyde

Viability assay

10.56499/jppres17.314_6.2.72

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Citations (7)

MODELOS ANIMALES DE TRAUMATISMO CRANEOENCEFÁLICO / Animal Models for Traumatic Brain Injury

Luis Arturo Fonseca-Fonseca Gilberto L. Pardo‐Andreu Yanier Núñez-Figueredo

El traumatismo craneoencefalico es uno de los problemas de salud publica mas relevantes, afecta anualmente a mas del 2% de la poblacion de Estados Unidos y representa una de las causas mas importantes de morbi-mortalidad, especialmente en la poblacion joven. Los modelos experimentales suponen en este momento la mejor herramienta que disponemos para estudiar las multiples alteraciones fisiopatologicas asociadas al dano cerebral traumatico asi como para la investigacion de nuevas estrategias terapeuticas. El objetivo del trabajo es proporcionar una revision de los diversos modelos experimentales de TCE que se han desarrollado para la investigacion del dano cerebral traumatico en condiciones in vivo , ademas de detallar los principales conocimientos fisiopatologicos y neuroconductuales obtenidos a partir de su aplicacion. Palabras clave: traumatismo craneoencefalico, modelos experimentales in vivo Abstract Traumatic brain injury is one of the most important problems of public health, annually affects more than 2% of the U.S. population and represents one of the major causes of morbidity and mortality, especially in young people. Experimental models assume at this point the best tool we have to study the multiple pathophysiological alterations associated with traumatic brain injury as well as research into new therapeutic strategies. The objective of this work is to provide a review of the various experimental models of TBI have been developed for the investigation of traumatic brain injury in vivo, as well as detailing the major pathophysiological and neurobehavioral knowledge gained from its application. Key words: Traumatic brain injury, experimental models in vivo

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KM-34, a Novel Antioxidant Compound, Protects against 6-Hydroxydopamine-Induced Mitochondrial Damage and Neurotoxicity

Neurotoxicity Research (2018)

Luis Arturo Fonseca-Fonseca Yanier Núñez-Figueredo Jeney Ramírez-Sánchez Maylin Wong Guerra Estael Ochoa

Hydroxydopamine

Neurotoxicity

Neurochemistry

Neuronal damage

10.1007/s12640-017-9851-5

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Citations (10)

A randomized, controlled, two-center preclinical trial assessing the efficacy of a new benzodiazepine–dihydropyridine hybrid molecule (JM-20) in rodent models of ischemic stroke

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Jeney Ramírez-Sánchez André Rex Sarah K. McCann Daniel Schulze Maylin Wong-Guerra

Abstract JM-20 is a novel multifunctional benzodiazepine molecule with potent neuroprotective effects in rat focal cerebral ischemia. To confirm previous results obtained in single laboratories with small sample sizes, and to provide a robust preclinical evidence base for potential clinical development in stroke, we have performed a two-center preclinical trial with sufficiently large group sizes to detect relevant effects, minimizing biases in experimental design as much as possible (randomization, blinding, predefined in- and exclusion criteria) and increasing external and construct validities by performing experimental focal cerebral ischemia by different surgeons in two different laboratories on two continents, including two species (480 mice and 55 rats), different suppliers, young, young adult, and mature adult animals (range 2 -16 months) as well as comorbid animals (diabetes). While JM-20 improved functional outcomes after middle cerebral artery occlusion in young adult mice at day 7 and appeared to reduce mortality (not statistically significant), it had no effect in mature adult or comorbid (STZ-induced diabetes) mice. Effect sizes, where statistically significant, were modest, and much lower than those reported in the previous studies. Meta-analysis of all individual mouse data did not reveal statistically significant different functional outcomes or mortalities between vehicle- and JM-20-treated animals, although neuroscores and survival were slightly better in JM-20-treated animals. In the less severe model of permanent cortical focal cerebral ischemia in rats, JM-20 significantly reduced brain infarction. We conclude that we were able to confirm the neuroprotective potential of JM-20. However, effect sizes were substantially lower as previously described in small, monocentric trials. Further study is needed to determine whether JM-20 could be effective in less severe cases of focal cerebral ischemia or when used in combination with thrombolysis.

Stroke

Blinding

10.1101/2024.03.08.584085

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Citations (1)

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

Neurological Research (2019)

Maylin Wong-Guerra Javier Jiménez-Martín Luis Arturo Fonseca-Fonseca Jeney Ramírez-Sánchez Yanay Montano-Peguero

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.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.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.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.

Memory Impairment

10.1080/01616412.2019.1573285

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Citations (23)

JM-20 treatment prevents neuronal damage and memory impairment induced by aluminum chloride in rats

NeuroToxicology (2021)

Maylin Wong-Guerra Yanay Montano-Peguero Jeney Ramírez-Sánchez Javier Jiménez-Martín Luis Arturo Fonseca-Fonseca

Memory Impairment

10.1016/j.neuro.2021.08.017

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Citations (18)

Novel arylidene malonate derivative, KM-34, showed neuroprotective effects on in vitro and in vivo models of ischemia/reperfusion