Banca de DEFESA: THÉO HENRIQUE DE LIMA VASCONCELLOS

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
STUDENT : THÉO HENRIQUE DE LIMA VASCONCELLOS
DATE: 27/08/2024
TIME: 13:00
LOCAL: Sala 208 do Bloco Zeta do Campus São Bernardo da Universidade Federal do ABC
TITLE:

ETHANOL AGGRAVATES NEUROINFLAMMATION TRIGGERED BY OXIDATIVE STRESS: THE ROLE OF INTRACELLULAR CALCIUM STORES IN RETINAL DEGENERATION

 

PAGES: 105
BIG AREA: Ciências Biológicas
AREA: Fisiologia
SUBÁREA: Fisiologia de Órgãos e Sistemas
SPECIALTY: Neurofisiologia
SUMMARY:

The retina is a photosensitive neuroepithelium in the inner eye region and is considered an integral component of the central nervous system (CNS). An imbalance in the physiological conditions or changes in the number of functional photoreceptors can lead to critical visual deficits. One of the most prevalent diseases worldwide that leads to vision impairment is retinitis pigmentosa (RP). RP is a multigenic retinal dystrophy, and among its causes of autosomal recessive RP (arRP) are mutations in the PDE6B gene, culminating in rod-type photoreceptors' initial cell death and cones' subsequent degradation. The mechanisms underlying primary rod cell death are not fully understood, although oxidative and metabolic stress, epigenetic factors, calcium dysregulation, and inflammatory responses could be related. Retinal neuroinflammation is a complex response that involves two major glial subtypes, Müller cells and microglia. The latter has great importance in RP, once this cell type is responsible for cleaning the cell debris from dying photoreceptors. In this context, microglia become activated, state that leads to several biochemical, functional, expression and morphologic changes, leading to exacerbated inflammation and further retinal damage. Therefore, targeting microglial activation could present new therapeutic strategies to slow or halt the disease progression. Intracellular calcium plays a pivotal role in regulating microglial cell processes, including proliferation, migration, modulation of the activation state, phagocytosis, morphology, and others. This study investigates the role of intracellular calcium stores and the potential neuroprotective effects of 2-aminoethyl diphenylborinate (2-APB), a store-operated calcium entry (SOCE) inhibitor. To this end, we proposed a a double-hit oxidative stress in vitro model. We also employed a mouse model of arRP (C3H/HeJ) to evaluate the effects of the pharmacological blocking of SOCE in vivo. Our analysis showed that the double-hit experimental model led to a strong neuroinflammatory reaction in microglia and macroglia cells. However, only microglia state is rescued by 2-APB treatment, with morphologic alterations, and prevalence of anti-inflammatory phenotype in these conditions. The number of neurons has increased, and these are more branched, possibly indicating a neuroprotection effect of the pharmacological intervention of SOCE by 2-APB in vitro. Conditioned medium provided by pure isolated microglia and Müller cells treated with double-hit stimuli showed that double-hit evokes inflammatory response from both cells, but only in the microglia 2-APB was able to revert the inflammatory response. The pharmacological intervention in arRP mice was performed using 2-APB by subretinal injection. Our results showed no alterations in retinal morphometry either in thickness or by TUNEL assay, with 2-APB not rescuing photoreceptor cells. The macroglial cells were not altered, but microglia presented altered morphology and a higher number in the outer retina compared to the vehicle. By multiplex cytokine analysis, it was possible to note a reduction of several cytokines, with a disorganization of the inflammatory response. Our results provide insights into the impact of SOCE regulation by 2-APB in microglial activity.

COMMITTEE MEMBERS:
Presidente - Interno ao Programa - 1676367 - ALEXANDRE HIROAKI KIHARA
Membro Titular - Examinador(a) Interno ao Programa - 1675708 - DANIELE RIBEIRO DE ARAUJO
Membro Titular - Examinador(a) Externo à Instituição - CAROLINA BELTRAME DEL DEBBIO - USP
Membro Suplente - Examinador(a) Interno ao Programa - 1227329 - CESAR AUGUSTO JOAO RIBEIRO
Membro Suplente - Examinador(a) Externo ao Programa - 1994696 - SILVIA HONDA TAKADA
Membro Suplente - Examinador(a) Externo à Instituição - GUILHERME SHIGUETO VILAR HIGA - USP
Membro Suplente - Examinador(a) Externo à Instituição - JULIANE MIDORI IKEBARA