Local supplementation of FGF-2 and BDNF in the epileptogenic hippocampus. Effects and delivery strategies

Among the epileptic syndromes, temporal lobe epilepsy (TLE) is the most common form in adults. It is the consequence of a brain damage (viral infection, stroke, trauma, cancer ...), capable of triggering a cascade of events culminating in the appearance of spontaneous seizures that are, in many cases, difficult to control with the usual drug therapy. The period that elapses between the initial insult and the development of spontaneous recurrent seizures (SRSs) is defined "epileptogenesis”. The cellular and tissue changes that occur during this phase mainly interest the hippocampal region and include: neurodegeneration, neurogenesis, neuroinflammation and reactive gliosis, angiogenesis, and reorganization of brain circuits. Recently, it was shown that supplementation of neurotrophic factors (NTFs), such as FGF-2 (fibroblast growth factor-2) and BDNF (brain derived neurotrophic factor), has anti-epileptogenic effects by reducing neuronal death, favoring a correct neurogenesis and restoring a proper balance between excitatory and inhibitory circuits. In the main study reported in this thesis, we examined if this treatment can also affect neuroinflammatory processes. We used the pilocarpine model, in which an episode of status epilepticus (SE) is followed by an epileptogenic lesion. After three days, herpes viral vectors expressing FGF-2 and BDNF were injected in the hippocampus. Four, 11 and 25 days after treatment (DAI), animals were sacrificed and their brains removed to analyze the expression of three markers of inflammation: IL-1β, GFAP (a marker of astrocytosis), Ox42 (marker of microglia). The results show a very marked reduction of IL-1β expression, evident as early as 4 days after inoculation of the viral vector, and delayed, but significant, attenuation of the other two markers. The sprouting of mossy fibers is another characteristic of the epileptic hippocampal tissue, in which the axons of granule cells form excitatory synapses with cells not usually innervated, forming a circuit that may favour hyperexcitability. The results show that treatment with neurotrophic factors reduce aberrant sprouting of nerve fibers, in a way that correlates with the attenuation of cellular damage. Parallel behavioral studies have also highlighted the ability of the treatment to reduce the frequency and severity of SRSs that, in this model, begin to occur about 21 days after status epilepticus. Despite the promising results, clinical applicability of neurotrophic factors is limited by the choice of an appropriate route of administration. In the experiments reported in this thesis, herpes viral vectors have been used. These vectors were replication defective and engineered to express the two NTFs. However, their residual toxicity makes them unsuitable for human application. Stem cells modified to express genes of interest, including mesangioblasts (MABs), have demonstrated, in vitro, the ability to promote differentiation, survival and neuronal function. Last but not least, the ability to localize in the damaged site when systemically administered makes these cells viable alternatives to more invasive treatments. Although further investigations are required, the results collected in this thesis are an important contribution to the understanding of the multiple effects of NTFs. In addition, the characterization of an alternative and more applicable route of administration renders gene therapy with neurotrophic factor more applicable for the treatment of several neurodegenerative diseases

Systematic Review and Critical Analysis of Cost Studies Associated with Parkinson's Disease

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide, affecting more than four million people. Typically, it affects individuals above 45, when they are still productive, compromising both aging and quality of life. Therefore, the cost of the disease must be identified, so that the use of resources can be rational and efficient. Additionally, in Brazil, there is a lack of research on the costs of neurodegenerative diseases, such as PD, a gap addressed in this study. This systematic review critically addresses the various methodologies used in original research around the world in the last decade on the subject, showing that costs are hardly comparable. Nonetheless, the economic and social impacts are implicit, and important information for public health agents is provided.Hosp Israelita Albert Einstein, Programa Posgrad, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Movement Disorders Dept Neurol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo UNIFESP, Sao Paulo, SP, BrazilHosp Israelita Albert Einstein, Neurol Program, Sao Paulo, SP, BrazilMovement Disorders Department in Neurology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, BrazilUniversidade Federal de São Paulo (UNIFESP), São Paulo, SP, BrazilWeb of Scienc

Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures

Under certain experimental conditions, neurotrophic factors may reduce epileptogenesis. We have previously reported that local, intrahippocampal supplementation of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) increases neurogenesis, reduces neuronal loss, and reduces the occurrence of spontaneous seizures in a model of damage-associated epilepsy. Here, we asked if these possibly anti-epileptogenic effects might involve anti-inflammatory mechanisms. Thus, we used a Herpes-based vector to supplement FGF-2 and BDNF in rat hippocampus after pilocarpine-induced status epilepticus that established an epileptogenic lesion. This model causes intense neuroinflammation, especially in the phase that precedes the occurrence of spontaneous seizures. The supplementation of FGF-2 and BDNF attenuated various parameters of inflammation, including astrocytosis, microcytosis and IL-1β expression. The effect appeared to be most prominent on IL-1β, whose expression was almost completely prevented. Further studies will be needed to elucidate the molecular mechanism(s) for these effects, and for that on IL-1β in particular. Nonetheless, the concept that neurotrophic factors affect neuroinflammation in vivo may be highly relevant for the understanding of the epileptogenic process

Jornada de presentación del Libro Blanco Desafíos 2030 del CSIC

Datos técnicos: 203 minutos, color, español. Ficha técnica: Gabinete de Presidencia CSIC y Departamento de ComunicaciónEl Consejo Superior de Investigaciones Científicas (CSIC) lanza 14 Temáticas estratégicas para coordinar equipos de investigación punteros y multidisciplinares que amplíen las fronteras del conocimiento en áreas como el origen de la vida, la composición de la materia, la exploración del espacio, el funcionamiento del cerebro, la transición energética, la sociedad global y el impacto del cambio global, entre otros. Estas temáticas funcionarán como grandes equipos de investigación para potenciar la sinergia entre áreas del conocimiento que logren objetivos a largo plazo. Las nuevas Temáticas estratégicas han sido impulsadas desde la Vicepresidencia de Investigación Científica y Técnica del CSIC, con la colaboración de las Comisiones de Áreas globales, y durante el último año ha supuesto un gran esfuerzo colaborativo de más de 1.100 investigadores pertenecientes a 112 centros del CSIC, así como colaboradores externos de otros Organismos Públicos de Investigación y Universidades, que han contribuido activamente a identificar estos retos para los próximos años, así como su evolución en el horizonte 2030.N