Research projects and collaborations

Effects of the pharmacological administration of ketamine in experimental depression treatment

Description: The rapid antidepressant effect of ketamine, an NMDA receptor antagonist, is one of the major breakthroughs in psychopharmacology in the last decade. The aim of this study is to find how the drug produces such an antidepressant effect. Using behavioral, biochemical and histological techniques, as well as microPET, we will observe the functional and biological changes associated with depression and its promising treatment in preclinical trials.

Members: Léder Leal Xavier (supervisor), Pedro Porto Alegre Baptista (doctoral student).

Read the article published on the topic:

Antidepressant Effects of Ketamine Are Not Related to 18 F-FDG Metabolism or Tyrosine Hydroxylase Immunoreactivity in the Ventral Tegmental Area of Wistar Rats.

In vivo molecular imaging of the migration, distribution and survival of stem cells in an animal model of epilepsy.

Description: In this project, molecular imaging will allow monitoring transplanted stem cells by molecular evaluation of biological processes of living cells and tissues, using the reporter gene HSV1-sr39tk and radiopharmaceutical 18F-FHBG. This technique will allow the analysis of radioactively labeled substrates from their interaction with the product of the permanent expression of a foreign gene inserted into a particular cell group, with the possibility of revealing the location, survival and migration of stem cells transplanted into in vivo models.

Members: Jaderson Costa Da Costa (Coordinator), Cristina Maria Moriguchi Jeckel, Mara Lise Zanini, David B. Stout, Guido Lenz, Samuel Greggio, Gianina Teribele Venturin, Louise Mross Hartmann, Marcos Alba, Gabriele Zanirati.
Funding: National Council for Scientific and Technological Development

Read the articles published on the topic:

Transplantation of bone marrow mononuclear cells modulates hippocampal expression of growth factors in chronically epileptic animals.

Bone marrow mononuclear cells reduce seizure frequency and improve cognitive outcome in chronic epileptic rats. 

Antiepileptic and neuroprotective effects of human umbilical cord blood mononuclear cells in a pilocarpine-induced epilepsy model. 

Transplantation of bone marrow mononuclear cells decreases seizure incidence, mitigates neuronal loss and modulates pro-inflammatory cytokine production in epileptic rats. 

Prevention of seizures and reorganization of hippocampal functions by transplantation of bone marrow cells in the acute phase of experimental epilepsy.

Comparison of the use of different matrices in the transplantation of human iPS-derived neural stem cells in a rat model of subacute spinal cord injury.

Description: Developing a protocol for the transplantation of human neural stem cells into rat models of spinal cord injury, testing different matrices to optimize survival, cell differentiation into neurons and oligodendrocytes, and integration of these cells to the injured medullary tissue.

Members: Jaderson Costa Da Costa (Coordinator), Asdrubal Falavigna, Simone Denise Salamoni, Denise Cantarelli Machado, Ricardo Vaz Breda, Léder Leal Xavier, Daniel Rodrigo Marinowic, Guido Lenz, Samuel Greggio, Gianina Teribele Venturin, Célia Regina Ribeiro da Silva Carlini, Karolyn Sassi Ogliari, Nara Regina de Souza Basso, Alessandra Deise Sebben, Michelle Flores Domingues, Fabrizio Blank Loth, Chariston Dal Bello, Dênis Reis de Assis, Zaquer Suzana Munhoz Costa-Ferro.

Funding: National Council for Scientific and Technological Development

Read the articles published on the topic:

The expression of pluripotency genes and neuronal markers after neurodifferentiation in fibroblasts co-cultured with human umbilical cord blood mononuclear cells.

Two intrathecal transplants of bone marrow mononuclear cells produce motor improvement in an acute and severe model of spinal cord injury.

Assessment of the permeability of the blood-brain barrier in an experimental model of reversible posterior encephalopathy syndrome through neuroimaging.

Project Coordinator: Luiz Carlos Porcello Marrone, MSc (PhD Project) and Jaderson Costa da Costa, PhD

Research Summary: The Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical-radiological state characterized by headache, altered level of consciousness, seizures and visual alteration, and is associated with a vasogenic edema in the brain white matter, affecting mostly the occipital and parietal lobes. The pathophysiology of PRES remains unknown in its entirety. Two theories are most prominent: the vasogenic theory and the cytotoxic theory.

Cytotoxic theory suggests that an intense and sudden increase in blood pressure would cause cerebral vasoconstriction, leading to endothelial damage caused by hypoxia, followed by vasospasm and formation of cytotoxic edema. However, the reversibility of lesions contradicts this hypothesis. The vasogenic theory would result from impairment of cerebral autoregulation, which would cause vasodilation, increased vascular permeability, and disruption of the blood-brain barrier causing vasogenic edema. The pathophysiology of PRES is also closely related with endothelial dysfunction, especially in cases without severe hypertension such as preeclampsia or cytotoxic therapies. Several factors can trigger this syndrome, most commonly: acute elevation of blood pressure, impaired kidney function and immunosuppressive therapy.

Other possible etiologies or related factors are: eclampsia, systemic lupus erythematosus (SLE), transplants, neoplasia and its treatment, systemic infections, acute or chronic kidney disease. In a previous project, we carried out an anatomic-pathologic study of animals which were submitted to surgical procedures aiming to mimic PRES. In the study, we found changes in the permeability of the blood-brain barrier in some animals submitted to surgery. However, we could not prove the reversibility of brain injury. There is no established experimental model of PRES proving reversibility.

The objective of the current study is to develop an experimental model of PRES proving that the permeability of the blood-brain barrier is reversible. An experimental model of PRES will be developed using the Reduced Uterine Perfusion Pressure surgical technique, with the placement of a silver clip in the aorta and uterine arteries. Animals undergoing this procedure will be examined by neuroimaging every 48 hours for assessment of the reversibility of the edema. A database will be prepared, and statistical analysis of the results will be conducted using Epi-Info.

With the establishment of an experimental model of cerebral edema reversibility, new research possibilities will arise in this field for the earlier reversal of edema.

Read the articles published on the topic:

Blood-Brain Barrier Breakdown in Reduced Uterine Perfusion Pressure: A Possible Model of Posterior Reversible Encephalopathy Syndrome

Posterior Reversible Encephalopathy Syndrome in a Child with Acute Lymphoblastic

Posterior Reversible encephalopathy syndrome: differences between pregnant and non-pregnant patients

Posterior Reversible Encephalopathy Syndrome Associated with FOLFOX Chemotherapy

Posterior Reversible Encephalopathy Syndrome Following a Scorpion Sting

Posterior reversible encephalopathy syndrome

Gemcitabine Monotherapy Associated with Posterior Reversible Encephalopathy Syndrome

Effects of umbilical cord blood stem cell transplantation in the treatment of newborn experimental models subjected to the germinal/intraventricular matrix hemorrhage model

Project Coordinator: Pâmella Nunes Azevedo, PhD candidate (Project developed during the Master’s degree)

Research Summary: Germinal/intraventricular matrix hemorrhage (HMG/IV) is the most common neurological complication of neonates, affecting about 50% of premature infants born with less than 34 weeks of gestation or weighing less than 1500g. This event is a major cause of mortality and morbidity in infants. Statistics suggest that infants who have hemorrhagic lesions of moderate to severe degree are highly prone to developing post-hemorrhagic hydrocephalus, hemiplegia, epilepsy, cerebral palsy and mental retardation, while those affected by mild injuries are at risk of developmental disabilities.

Treatment of HMG/IV consists of supportive measures and does not address restoration of the neonatal brain injury process. This encourages research aimed at finding alternative ways of maintaining neuronal integrity during the disease process. This study investigates whether human umbilical cord blood stem cells have therapeutic potential in preventing motor and cognitive deficit in newborn rats submitted to the HMG/IV model.

Read the article published on the topic:

A novel preclinical rodent model of collagenase-induced germinal matrix/intraventricular hemorrhage.