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[Display omitted] • IGF-1 gene therapy improves cognitive deficits caused by 6-hydroxydopamine. • IGF-1 gene therapy increases the expression level of tyrosine hydroxylase in the caudate-putamen. • IGF-1 gene therapy modifies parameters of microglia and astrocyte phenotypes. Cognitive impairment in Parkinson's disease is considered an indicator of the prodromal stages of this condition, occurring prior to the onset of classic and pathognomonic motor symptoms. Among other factors, neuroinflammation is increasingly recognized as a potential mediator of this neurodegenerative process, and glial cells are directly involved. However, the use of neurotrophic factors is associated with neuroprotection and cognitive improvements. Among all those factors, insulin-like growth factor 1 (IGF-1) has attracted considerable attention. In this study, we aimed to investigate the effect of IGF-1 gene therapy in an early animal model of 6-hydroxidopamine (6-OHDA)- induced parkinsonism. For this purpose, we employed male Wistar rats. The animals were first divided into two groups according to the bilateral injection into de Caudate Putamen unit (CPu):(a) VEH group (vehicle solution) and (b) 6-OHDA group (neurotoxic solution). After that, the animals in each group were divided, according to the bilateral injection into the dorsal hippocampus, in a control group (who received a control virus RAd-DSRed) and an experimental group (who received a therapeutic virus (RAd-IGF1). After three weeks of exposure to 6-OHDA, our study showed that IGF-1 gene therapy improved cognitive deficits related to short-term and spatial working memory, it also increased expression levels of tyrosine hydroxylase in the CPu. In addition, the therapy resulted in significant changes in several parameters (area, perimeter, roundness, ramification, and skeleton ́s analyses) related to microglia and astrocyte phenotypes, particularly in the CPu and dorsal hippocampal areas. Our data support the use of IGF-1 as a therapeutic molecule for future gene transfer interventions, that will contribute to a better understanding of the mechanisms correlating cognitive function and inflammatory process. [ABSTRACT FROM AUTHOR]

Highlights • Neurodegenerative diseases are threatening conditions that affect life-quality and life-span of the affected patients. • ALDH2 is a critical enzyme involved in neurotoxic mechanisms of PD and AD. • 4-HNE is considered a fundamental signaling molecules in the pathogenesis of AD and its detoxification depends on ALDH2. • ALDH2 activation is proposed as a therapeutic approach for PD since the enzyme plays a crucial role in mitochondrial normal function maintenance. Abstract Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Glial cells are directly or indirectly affected by estradiol and by different estrogenic compounds, such as selective estrogen receptor modulators. Acting on oligodendrocytes, astrocytes and microglia, estrogens regulate remyelination, edema formation, extracellular glutamate levels and the inflammatory response after brain injury. In addition, estradiol induces the expression and release of growth factors by glial cells that promote neuronal survival. Therefore, glial cells are important players in the neuroprotective and reparative mechanisms of estrogenic compounds. [ABSTRACT FROM AUTHOR]

It is well‐established that females live longer than males. Paradoxically, women tend to have poorer health, a condition often named sex frailty. The aim of this study was to evaluate possible frailty predictors in older mice in a sex‐specific manner, in order to employ these predictors to follow‐up therapy efficiency. To further evaluate therapy effects, we also investigated the use of neurotrophic insulin‐like growth factor 1 (IGF‐1) gene therapy and its correlation with the expression of this frailty and emotional behaviour. In order to evaluate frailty, we employed two different approaches. We performed a frailty assessment through a 31‐Item Clinical Frailty Index and through a Performance‐Based 8‐Item Frailty Index. Our results show that both indexes are in concordance to evaluate sex differences, but they do not correlate when evaluating IGF‐1 therapy effects. Moreover, in order to reduce test‐to‐test variability for measures of dependent variables, we compared open field results across studies assessing sex and treatment by means of the z‐score normalization. The data show that regular open field parameters submitted to z‐score normalization analysis could be a useful tool to identify sex differences in ageing mice after growth factor therapies. Taking this into account, sex is a factor that influences the incidence and/or nature of all major complex diseases; the main outcome of our investigation is the development of an efficient tool that compares the use of different frailty index calculations. This represents an important strategy in order to identify sex differences and therapy efficiency in ageing models. [ABSTRACT FROM AUTHOR]