Effect of deep brain stimulation and cannabidiol treatment in the subthalamic nucleus on the motors and non-Motors symptoms in the experimental model of Parkinson Disease

• Grant number: 17/13560-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2018
• End date: April 30, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Norberto Cysne Coimbra
• Grantee: Priscila Medeiros de Freitas
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Parkinson's disease (PD) is a progressive disorder of movement associated with the dopaminergic depletion of the substantia nigra, pars compacta (SNpc). The basal nuclei and motor cortex connexions impairments lead to clinical manifestations like tremor, postural stiffness, bradykinesia and postural instability. However, non-motor symptoms, for example, depression, anxiety, cognitive changes, olfactory disorders and chronic pain may also be present in PD. In fact, manifestations of non-motor symptoms affect the quality of life of patients with PD. Recent studies suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) could improve the motor, pain, and emotional state of PD patients. Indeed, the pathophysiology and Neuropsychopharmacological mechanisms of PD symptoms need to be better clarified. Therefore, we will evaluate the motor and non-motor symptoms of parkinsonoid syndrome using the animal model of PD with microinjections of the 6-hydroxydopamine (6-OHDA) neurotoxin or sham procedure (without neurotoxin) in the Striatum. The present project will be divided as follows: 1st: Neuroanatomical study: to evaluate the anatomic connections between STN with motor areas [as motor cortex (M1) and basal nuclei] and non-motor areas [as medial prefrontal cortex (mPFC)] will be microinjected BDA 3.000 in STN. 2nd: Neuroelectrophysiological study: we will use the multiuser equipment (Thomas Recording) to stimulate the STN and simultaneously register the neuronal activity of M1 and mPFC [cingulate cortex (Cg1), prelimbic (PrL) and infralimbic (IFL)] in lesioned animals with 6-OHDA or sham. 3rd: Neurophysiological study: To evaluate the effect of the STN neurostimulation on the motor and non-motor aspects of PD, the electrical stimulus (DBS at 20¼A or 100¼A for 15s) in different subareas (motor and non-motor) of the NST in animals treated with or without 6-OHDA. Thus, motor behaviours, like apomorphine-induced rotation test and cylinder test will be performed. The experiments related to non-motor behaviour, such as olfactory discrimination test (sensory), sucrose preference test (depression), recognition test (attention and memory), von Frey test (mechanical allodynia) and acetone test (sensitivity to cold) will also be performed. In order to evaluate the effect of cannabidiol (CBD) treatment on the motor and non-motor components of PD, the behavioural tests mentioned before will be carried out after the pretreatment of the STN with CBD (at 15, 30 and 60 nmol) in an experimental model of Parkinson's disease in Wistar rats. (AU)

Scientific publications

(11)

(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)

MEDEIROS, PRISCILA; OLIVEIRA-SILVA, MARIANA; NEGRINI-FERRARI, SYLMARA ESTHER; MEDEIROS, ANA CAROLINA; ELIAS-FILHO, DAOUD HIBRAIM; COIMBRA, NORBERTO CYSNE; DE FREITAS, RENATO LEONARDO. CB1-cannabinoid-, TRPV1-vanilloid- and NMDA-glutamatergic-receptor-signalling systems interact in the prelimbic cerebral cortex to control neuropathic pain symptoms. Brain Research Bulletin, v. 165, p. 118-128, DEC 2020. (17/13560-5, 09/17258-5, 12/25167-2, 14/11869-0, 14/07902-2, 13/12916-0)

MEDEIROS, PRISCILA; NEGRINI-FERRARI, SYLMARA ESTHER; PALAZZO, ENZA; MAIONE, SABATINO; FERREIRA, SERGIO HENRIQUE; DE FREITAS, RENATO LEONARDO; COIMBRA, NORBERTO CYSNE. N-methyl-d-aspartate Receptors in the Prelimbic Cortex are Critical for the Maintenance of Neuropathic Pain. Neurochemical Research, v. 44, n. 9, p. 2068-2080, SEP 2019. (14/11869-0, 12/25167-2, 13/08216-2, 13/12916-0, 11/19670-0, 17/13560-5, 09/17258-5, 14/07902-2)

CALVO, FABRICIO; ALMADA, RAFAEL CARVALHO; DOS ANJOS-GARCIA, TAYLLON; FALCONI-SOBRINHO, LUIZ LUCIANO; PASCHOALIN-MAURIN, TATIANA; BAZAGLIA-DE-SOUSA, GUILHERME; MEDEIROS, PRISCILA; DA SILVA, JULIANA ALMEIDA; LOBAO-SOARES, BRUNO; COIMBRA, NORBERTO CYSNE. Panicolytic-like effect of mu(1)-opioid receptor blockade in the inferior colliculus of prey threatened by Crotalus durissus terrificus pit vipers. JOURNAL OF PSYCHOPHARMACOLOGY, v. 33, n. 5, p. 577-588, MAY 2019. (09/02458-9, 13/10984-8, 17/11855-8, 17/13560-5, 12/25167-2, 12/03798-0, 07/01174-1, 15/10313-1, 12/22681-7)

CALVO, FABRICIO; ALMADA, RAFAEL CARVALHO; DA SILVA, JULIANA ALMEIDA; MEDEIROS, PRISCILA; SOARES, JR., RAIMUNDO DA SILVA; DE PAIVA, YARA BEZERRA; RONCON, CAMILA MARRONI; COIMBRA, NORBERTO CYSNE. The Blockade of mu(1)- and kappa-Opioid Receptors in the Inferior Colliculus Decreases the Expression of Panic Attack-Like Behaviours Induced by Chemical Stimulation of the Dorsal Midbrain. NEUROPSYCHOBIOLOGY, v. 78, n. 4, p. 218-228, NOV 2019. (09/54014-7, 12/23238-0, 15/10313-1, 09/02458-9, 07/01174-1, 12/25167-2, 12/03798-0, 17/13560-5, 12/22681-7)

P. MEDEIROS; I.R. DOS SANTOS; A.C. MEDEIROS; J.A. DA SILVA; S.H. FERREIRA; R.L. DE FREITAS; N.C. COIMBRA. Indomethacin attenuates mechanical allodynia during the organization but not the maintenance of the peripheral neuropathic pain induced by nervus ischiadicus chronic constriction injury. Brazilian Journal of Medical and Biological Research, v. 53, n. 5, 2020-04-27. (09/17258-5, 13/12916-0, 14/11869-0, 17/13560-5, 13/08216-2, 12/25167-2, 14/07902-2, 11/19670-0)

MEDEIROS, PRISCILA; DOS SANTOS, IEDA REGINA; MATIAS JUNIOR, IVAIR; PALAZZO, ENZA; DA SILVA, JOSE APARECIDO; MACHADO, HELIO RUBENS; FERREIRA, SERGIO HENRIQUE; MAIONE, SABATINO; COIMBRA, NORBERTO CYSNE; DE FREITAS, RENATO LEONARDO. An Adapted Chronic Constriction Injury of the Sciatic Nerve Produces Sensory, Affective, and Cognitive Impairments: A Peripheral Mononeuropathy Model for the Study of Comorbid Neuropsychiatric Disorders Associated with Neuropathic Pain in Rats. PAIN MEDICINE, v. 22, n. 2, p. 338-351, FEB 2021. (11/19670-0, 13/08216-2, 13/12916-0, 17/13560-5, 14/11869-0, 12/25167-2, 14/07902-2, 09/17258-5)

DE MELLO ROSA, GUSTAVO HENRIQUE; ULLAH, FARHAD; DE PAIVA, YARA BEZERRA; DA SILVA, JULIANA ALMEIDA; BRANCO, LUIZ GUILHERME S.; CORRADO, ALEXANDRE PINTO; MEDEIROS, PRISCILA; COIMBRA, NORBERTO CYSNE; BIAGIONI, AUDREY FRANCESCHI. Ventrolateral periaqueductal gray matter integrative system of defense and antinociception. PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, v. 474, n. 4, p. 12-pg., 2022-02-24. (15/10313-1, 17/13560-5, 16/18218-0, 16/17681-9, 09/54014-7, 14/10742-7)

MELO-THOMAS, LIANA; TACKEN, LARS; RICHTER, NICOLE; DE ALMEIDA, DAVINA; RAPOSO, CATARINA; DE MELO, SILVANA REGINA; THOMAS, UWE; DE PAIVA, YARA BEZERRA; MEDEIROS, PRISCILA; COIMBRA, NORBERTO CYSNE; et al. Lateralization in Hemiparkinsonian Rats Is Affected by either Deep Brain Stimulation or Glutamatergic Neurotransmission in the Inferior Colliculus. ENEURO, v. 9, n. 4, p. 19-pg., 2022-07-01. (17/19799-0, 19/11448-9, 20/15050-7, 15/04194-0, 17/13560-5)

MEDEIROS, ANA C.; MEDEIROS, PRISCILA; FREITAS, RENATO L.; SILVA JUNIOR, PEDRO ISMAEL; COIMBRA, NORBERTO C.; DOS SANTOS, WAGNER F.. Acanthoscurria gomesiana spider-derived synthetic mygalin in the dorsal raphe nucleus modulates acute and chronic pain. JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, v. 35, n. 10, AUG 2021. (09/54014-7, 17/13560-5, 13/12916-0, 12/25167-2, 09/17258-5, 14/11869-0)

NEGRINI-FERRARI, SYLMARA ESTHER; MEDEIROS, PRISCILA; MALVESTIO, RAFAEL BRAGHETTO; SILVA, MARIANA DE OLIVEIRA; MEDEIROS, ANA CAROLINA; COIMBRA, NORBERTO CYSNE; MACHADO, HELIO RUBENS; DE FREITAS, RENATO LEONARDO. The primary motor cortex electrical and chemical stimulation attenuates the chronic neuropathic pain by activation of the periaqueductal grey matter: The role of NMDA receptors. Behavioural Brain Research, v. 415, OCT 11 2021. (14/07902-2, 13/12916-0, 14/11869-0, 12/25167-2, 17/13560-5, 09/17258-5)

MALVESTIO, R. B.; MEDEIROS, P.; NEGRINI-FERRARI, S. E.; OLIVEIRA-SILVA, M.; MEDEIROS, A. C.; PADOVAN, C. M.; LUONGO, L.; MAIONE, S.; COIMBRA, N. C.; DE FREITAS, R. L.. Cannabidiol in the prelimbic cortex modulates the comorbid condition between the chronic neuropathic pain and depression-like behaviour in rats: The role of medial prefrontal cortex 5-HT1A and CB1 receptors. Brain Research Bulletin, v. 174, p. 323-338, SEP 2021. (14/16720-5, 12/25167-2, 17/13560-5, 14/26228-0, 09/17258-5, 14/07902-2)