Titolo della tesi: Study of the effect of antioxidant molecules on neuroinflammatory markers and on the cognitive-behavioral phenotype in a valproic acid (VPA)-induced autism model in zebrafish
The Autism Spectrum Disorder (ASD) is a common developmental
disorder characterized by persistent deficits in social communication and
social interaction across multiple contexts, and by restricted, repetitive
patterns of behavior, interests, or activities. Symptoms must be present in
the early developmental period and must cause clinically significant
impairment in social, occupational, or other important areas of
functioning. According to the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5), it is included in Neurodevelopmental
Disorders (NDDs), along with Attention Deficit/Hyperactivity Disorder
(ADHD), intellectual disabilities, communication disorders, specific
learning disorders and motor disorders, and with whom frequently
coexists. Despite its high worldwide incidence, the etiology remains
broadly undetermined. However, previous studies shed light on the
contribution of both genetic and environmental factors to the pathogenesis
of the disorder. Indeed, numerous genes, defined “ASD-risk genes”, most
of which are involved in the immunologic response within the Central
Nervous System (CNS), seem to have a role in the predisposition to
develop ASD and to determine a pro-inflammatory/pro-oxidative
environment, which have been frequently detected in autistic post-mortem
human brains. Among the environmental factors, great attention has been
paid to the early administration of Valproic Acid (VPA), an anti-seizure
drug. VPA exposure of pregnant women has been linked to an increase in
the risk of ASD, prompting the development of various VPA-induced
animal models, including zebrafish. The present project utilizes the well-
known VPA-induced zebrafish model of ASD to better determine the
minimal effective dose of VPA required to induce a stable autism-like
phenotype persisting into adulthood, and to investigate the possibility of
attenuating the phenotype through a drug repositioning assay. Molecular
and behavioral analyses were conducted to assess pro-neuroinflammatory
state, oxidative stress, and social behavior, both in larvae and adult fish. In
addition, we used β-glucans— natural compounds with anti-inflammatory
and antioxidant properties, already tested in other disease models— to
evaluate their ability to attenuate short- and long-term phenotypic
manifestations of ASD in our zebrafish model.