Epilepsies and neuropsyquiatric comorbidities: characterization of the effects of the treatment with cannabidiol and HUF-101 in in vivo and in vitro experimental models

• Grant number: 19/05957-8
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2019
• End date: July 31, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Norberto Garcia Cairasco
• Grantee: Norberto Garcia Cairasco
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• City of the host institution: Ribeirão Preto
• Associated researchers: Antonio Claudio Tedesco ; Maria de Fátima Leite ; Victor Rodrigues Santos
• Associated research grant(s): 19/16574-2 - Unraveling the molecular and genetic mechanisms of epilepsy, AP.R SPRINT
• Associated scholarship(s): 21/14198-3 - Epilepsies and neuropsychiatric comorbidities: characterization of cannabidiol and HUF-101 treatments in in vivo and in vitro experimental models os epilepsies, BP.TT; 20/02604-4 - EPILEPSIES AND NEUROPSYQUIATRIC COMORBIDITIES: CHARACTERIZATION OF THE EFFECTS OF THE TREATMENT WITH CANNABIDIOL AND HUF-101 IN IN VIVO AND IN VITRO EXPERIMENTAL MODELS, BP.TT

Abstract

In the current project we initially make an introduction to the history of the Wistar Audiogenic Rat (WAR) strain, developed by our group since the 1990s, and of the research with the epilepsies and neuropsyquiatric comorbidities involving this model. We introduce immediately after all the justification to search for novel antiepileptogenic and neuroprotection alternatives, because a significative part of the people with epilepsy (near 40%) are pharmacorresistant. In this context cannabidiol (CBD) and its fluorinated analogues (for example HUF-101) appear as important pharmacological alternatives. The hypotheses of this Project are: (1) CBD and its fluorinated analogue HUF-101 present neuroprotection, anticonvulsant and anxiolytic effects in experimental epilepsy models, such as: Status Epilepticus (SE) induced by intra-hipocampal microinjection of pilocarpine, model of Amygdala Rapid Kindling (ARK) and anticonvulsant and anxiolytic effect in models of generalized tonic-clonic (acute) and limbic (chronic) seizures in WARs, and their behavioral consequences, for example, increase of anxiety, respectively. (2) CBD displays different mechanisms of action, that can be mediated by non-conventional intra-cellular signaling pathways in neuronal models. (3) New systems of drug delivery (nanoparticles) can optimize the anticonvulsant and neuroprotection effect of CBD in the treatment of the epilepsies. In this context, the main goals of this project are (1) To evaluate the behavioral, electroencephalographic (EEGraphic) and histological effects of a unique dose of HUF-101, in different experimental models of epilepsies. (2). To evaluate the behavioral, cellular and molecular effects of CBD, after chronic administration, in acute and chronic audiogenic seizure models (WAR strain). (3) To investigate the effects of the chronic treatment with CBD on the main comorbidities associated to the epilepsies, initially with models of anxiety. (4) To elucidate de non-conventional signaling pathways activated by CBD and correlate them with the mechanisms of action in a neuronal cellular model and the epilepsies. (5) To develop, characterize and evaluate effects of the previous administration of CBD and HUF-101 in nanoparticles (CBDnp e HUFnp), in rats submitted to the model of SE induced by intra-hippocampal microinjection of pilocarpine, using behavioral, EEGraphic and histochemical tools. The preliminary results with in vivo and in vitro assays with CBD e HUF-101 are promising, both for the evaluation of their anti-convulsant, and their neuroprotection activities, as well as for the detection of the associated non-conventional cellular and molecular mechanisms of action. (AU)

Scientific publications

(18)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

LAZARINI-LOPES, WILLIAN; DO VAL-DA SILVA, RAQUEL A.; DA SILVA-JUNIOR, RUI M. P.; LEITE, JOAO P.; GARCIA-CAIRASCO, NORBERTO. The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: From behavior and mechanisms to clinical insights. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 111, p. 166-182, APR 2020. (19/05957-8, 14/50891-1, 19/00849-2)

GARCIA-CAIRASCO, NORBERTO; PODOLSKY-GONDIM, GUILHERME; TEJADA, JULIAN. Searching for a paradigm shift in the research on the epilepsies and associated neuropsychiatric comorbidities. From ancient historical knowledge to the challenge of contemporary systems complexity and emergent functions. Epilepsy & Behavior, v. 121, n. B, AUG 2021. (19/05957-8, 14/50891-1)

LAZARINI-LOPES, WILLIAN; DO VAL-DA SILVA, RAQUEL A.; DA SILVA-JUNIOR, RUI M. P.; CUNHA, ALEXANDRA O. S.; GARCIA-CAIRASCO, NORBERTO. Cannabinoids in Audiogenic Seizures: From Neuronal Networks to Future Perspectives for Epilepsy Treatment. FRONTIERS IN BEHAVIORAL NEUROSCIENCE, v. 15, FEB 11 2021. (19/05957-8, 19/00849-2, 14/50891-1)

LAZARINI-LOPES, WILLIAN; SILVA-CARDOSO, GLEICE KELLI. Neuroplastic alterations in cannabinoid receptors type 1 (CB1) in animal models of epileptic seizures. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 137, p. 17-pg., 2022-05-05. (19/05957-8, 18/06877-5, 21/14198-3)

GOMEZ-NIETO, RICARDO; LOPEZ, DOLORES E.; GARCIA-CAIRASCO, NORBERTO. Editorial: Challenges and Conundrums in Cannabinoid-Based Treatments for Epilepsy Syndromes and Associated Neurobehavioral Comorbidities. FRONTIERS IN BEHAVIORAL NEUROSCIENCE, v. 15, p. 4-pg., 2021-11-11. (19/05957-8, 19/16574-2, 14/50891-1, 19/00849-2, 19/02787-4)

ZANONA, QUERUSCHE KLIPPEL; MARCONI, GABRIEL ALVES; COUTO PEREIRA, NATIVIDADE DE SA; LAZZAROTTO, GABRIELA; FERREIRA DONATTI, ANA LUIZA; CORTES DE OLIVEIRA, JOSE ANTONIO; GARCIA-CAIRASCO, NORBERTO; CALCAGNOTTO, MARIA ELISA. Absence-like Seizures, Cortical Oscillations Abnormalities and Decreased Anxiety-like Behavior in Wistar Audiogenic Rats with Cortical Microgyria. Neuroscience, v. 500, p. 15-pg., 2022-08-17. (19/05957-8)

LAZARINI-LOPES, WILLIAN; SILVA-CARDOSO, GLEICE KELLI; CORTES DE OLIVEIRA, JOSE ANTONIO; CORREA PASSOS, LUIZ AUGUSTO; SALGADO, ANDREIA RUIS; RODRIGUES DEMOLIN, DANIELE MASSELLI; ANDRADE LEITE-PANISSI, CHRISTIE RAMOS; GARCIA-CAIRASCO, NORBERTO; COIMBRA, NORBERTO CYSNE. Inherited pain hypersensitivity and increased anxiety-like behaviors are associated with genetic epilepsy in Wistar Audiogenic Rats: Short- and long-term effects of acute and chronic seizures on nociception and anxiety. Epilepsy & Behavior, v. 141, p. 13-pg., 2023-03-10. (21/14198-3, 21/13622-6, 20/15050-7, 21/14073-6, 19/05957-8, 18/06877-5)

ALVES, SUELEN SANTOS; PATRICIO DA SILVA JUNIOR, RUI MILTON; DELFINO-PEREIRA, POLIANNA; ALVES GOULART PEREIRA, MARILIA GABRIELLA; VASCONCELOS, ISRAEL; SCHWAEMMLE, HANNA; MAZZEI, RODRIGO FOCOSI; CARLOS, MAIKO LUIZ; ESPREAFICO, ENILZA MARIA; TEDESCO, ANTONIO CLAUDIO; et al. A Genetic Model of Epilepsy with a Partial Alzheimer's Disease-Like Phenotype and Central Insulin Resistance. Molecular Neurobiology, v. 59, n. 6, p. 17-pg., 2022-04-04. (19/05957-8, 14/50891-1, 19/16574-2, 19/02787-4, 19/00849-2, 17/21155-3)

LAZARINI-LOPES, WILLIAN; DA SILVA-JUNIOR, RUI M. P.; SERVILHA-MENEZES, GABRIEL; DO VAL-DA SILVA, RAQUEL A.; GARCIA-CAIRASCO, NORBERTO. Cannabinoid Receptor Type 1 (CB1R) Expression in Limbic Brain Structures After Acute and Chronic Seizures in a Genetic Model of Epilepsy. FRONTIERS IN BEHAVIORAL NEUROSCIENCE, v. 14, DEC 21 2020. (19/00849-2, 19/02787-4, 14/50891-1, 19/05957-8)

SERVILHA-MENEZES, GABRIEL; GARCIA-CAIRASCO, NORBERTO. A complex systems view on the current hypotheses of epilepsy pharmacoresistance. EPILEPSIA OPEN, v. N/A, p. 15-pg., 2022-03-11. (19/02787-4, 19/05957-8, 14/50891-1)

LAZARINI-LOPES, WILLIAN; SILVA-CARDOSO, GLEICE KELLI; ANDRADE LEITE-PANISSI, CHRISTIE RAMOS; GARCIA-CAIRASCO, NORBERTO. Increased TRPV1 Channels and FosB Protein Expression Are Associated with Chronic Epileptic Seizures and Anxiogenic-like Behaviors in a Preclinical Model of Temporal Lobe Epilepsy. BIOMEDICINES, v. 10, n. 2, p. 19-pg., 2022-02-01. (18/06877-5, 19/05957-8)

ALVES, SUELEN SANTOS; ANTONIO CORTES DE OLIVEIRA, JOSE; LAZARINI-LOPES, WILLIAN; SERVILHA-MENEZES, GABRIEL; GRIGORIO-DE-SANT'ANA, MARIANA; DEL VECCHIO, FLAVIO; FOCOSI MAZZEI, RODRIGO; SOUSA ALMEIDA, SEBASTIAO; MILTON PATRICIO DA SILVA JUNIOR, RUI; GARCIA-CAIRASCO, NORBERTO. Audiogenic Seizures in the Streptozotocin-Induced Rat Alzheimer's Disease Model. JOURNAL OF ALZHEIMER'S DISEASE, v. 94, n. 3, p. 18-pg., 2023-01-01. (21/13622-6, 14/50891-1, 17/21155-3, 19/02787-4, 19/00849-2, 19/05957-8)

ALVES, SUELEN SANTOS; SERVILHA-MENEZES, GABRIEL; ROSSI, LETICIA; DA SILVA JUNIOR, RUI MILTON PATRICIO; GARCIA-CAIRASCO, NORBERTO. Evidence of disturbed insulin signaling in animal models of Alzheimer's disease. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, v. 152, p. 23-pg., 2023-09-01. (21/14907-4, 14/50891-1, 17/21155-3, 19/02787-4, 19/00849-2, 19/05957-8)

TILELLI, CRISTIANE QUEIXA; FLORES, LARISSA RIBEIRO; COTA, VINICIUS ROSA; DE CASTRO, OLAGIDE WAGNER; GARCIA-CAIRASCO, NORBERTO. Amygdaloid complex anatomopathological findings in animal models of status epilepticus. Epilepsy & Behavior, v. 121, n. B, AUG 2021. (14/50891-1, 19/05957-8)

VALENTIM-LIMA, EVANDRO; DE OLIVEIRA, JOSE ANTONIO CORTES; ANTUNES-RODRIGUES, JOSE.; REIS, LUIS CARLOS; GARCIA-CAIRASCO, NORBERTO; MECAWI, ANDRE S.. Neuroendocrine changes in the hypothalamic-neurohypophysial system in the Wistar audiogenic rat (WAR) strain submitted to audiogenic kindling. Journal of Neuroendocrinology, v. 33, n. 7, SI, JUL 2021. (19/05957-8, 14/50891-1, 14/15218-4, 13/09799-1)

ALVES, SUELEN SANTOS; PATRICIO DA SILVA-JUNIOR, RUI MILTON; SERVILHA-MENEZES, GABRIEL; HOMOLAK, JAN; SALKOVIC-PETRISIC, MELITA; GARCIA-CAIRASCO, NORBERTO. Insulin Resistance as a Common Link Between Current Alzheimer's Disease Hypotheses. JOURNAL OF ALZHEIMER'S DISEASE, v. 82, n. 1, p. 71-105, 2021. (19/00849-2, 19/05957-8, 14/50891-1, 19/02787-4)

SILVA-CARDOSO, GLEICE K.; LAZARINI-LOPES, WILLIAN; HALLAK, JAIME E.; CRIPPA, JOSE A.; ZUARDI, ANTONIO W.; GARCIA-CAIRASCO, NORBERTO; LEITE-PANISSI, CHRISTIE R. A.. Cannabidiol effectively reverses mechanical and thermal allodynia, hyperalgesia, and anxious behaviors in a neuropathic pain model: Possible role of CB1 and TRPV1 receptors. Neuropharmacology, v. 197, OCT 1 2021. (19/05957-8, 18/06877-5, 14/50891-1)

GARCIA-CAIRASCO, N.. My homage to professor Steve C. Schachter: Human expressions in the epilepsies, neuro-science, and the arts. Epilepsy & Behavior, v. 137, p. 2-pg., 2022-12-01. (19/05957-8, 14/50891-1)