Brain and spinal cord trauma: what we know about the therapeutic potential of insulin growth factor 1 gene therapy.

Although little attention has been paid to cognitive and emotional dysfunctions observed in patients after spinal cord injury, several reports have described impairments in cognitive abilities. Our group also has contributed significantly to the study of cognitive impairments in a rat model of spinal cord injury. These findings are very significant because they demonstrate that cognitive and mood deficits are not induced by lifestyle changes, drugs of abuse, and combined medication. They are related to changes in brain structures involved in cognition and emotion, such as the hippocampus. Chronic spinal cord injury decreases neurogenesis, enhances glial reactivity leading to hippocampal neuroinflammation, and triggers cognitive deficits. These brain distal abnormalities are recently called tertiary damage. Given that there is no treatment for Tertiary Damage, insulin growth factor 1 gene therapy emerges as a good candidate. Insulin growth factor 1 gene therapy recovers neurogenesis and induces the polarization from pro-inflammatory towards anti-inflammatory microglial phenotypes, which represents a potential strategy to treat the neuroinflammation that supports tertiary damage. Insulin growth factor 1 gene therapy can be extended to other central nervous system pathologies such as traumatic brain injury where the neuroinflammatory component is crucial. Insulin growth factor 1 gene therapy could emerge as a new therapeutic strategy for treating traumatic brain injury and spinal cord injury.

IGF1 gene therapy in middle-aged female rats delays reproductive senescence through its effects on hypothalamic GnRH and kisspeptin neurons.

The process of aging is the result of progressive loss of homeostasis and functional body impairment, including the central nervous system, where the hypothalamus plays a key role in regulating aging mechanisms. The consequences of aging include a chronic proinflammatory environment in the hypothalamus that leads to decreased secretion of gonadotropin-releasing hormone (GnRH) and impairs kisspeptin neuron functionality. In this work, we investigated the effect of insulin-like growth factor 1 (IGF1) gene therapy on hypothalamic kisspeptin/GnRH neurons and on microglial cells, that mediate the inflammatory process related with the aging process. The results show that IGF1 rats have higher kisspeptin expression in the anteroventral periventricular (AVPV) nucleus and higher immunoreactivity of GnRH in the arcuate nucleus and median eminence. In addition, IGF1-treated animals exhibit increased numbers of Iba1+ microglial cells and MHCII+/Iba1+ in the AVPV and arcuate nuclei. In conclusion, IGF1 gene therapy maintains kisspeptin production in the AVPV nucleus, induces GnRH release in the median eminence, and alters the number and reactivity of microglial cells in middle-aged female rats. We suggest that IGF1 gene therapy may have a protective effect against reproductive decline.

IGF-1 Gene Transfer Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain.

Brain aging is characterized by chronic neuroinflammation caused by activation of glial cells, mainly microglia, leading to alterations in homeostasis of the central nervous system. Microglial cells are constantly surveying their environment to detect and respond to diverse signals. During aging, microglia undergoes a process of senescence, characterized by loss of ramifications, spheroid formation, and fragmented processes, among other abnormalities. Therefore, the study of changes in microglia during is of great relevance to understand age-related declines in cognitive and motor function. We have targeted the deleterious effects of aging by implementing IGF-1 gene transfer, employing recombinant adenoviral vectors (RAds) as a delivery system. In this study, we performed intracerebroventricular (ICV) RAd-IGF-1 or control injection on aged female rats and evaluated its effect on caudate-putamen unit (CPu) gene expression and inflammatory state. Our results demonstrate that IGF-1 overexpression modified aged microglia of the CPu towards an anti-inflammatory condition increasing the proportion of double immuno-positive Iba1+Arg1+ cells. We also observed that phosphorylation of Akt was increased in animals treated with RAd-IGF-1. Moreover, IGF-1 gene transfer was able to regulate CPu pro-inflammatory environment in female aged rats by down-regulating the expression of genes typically overexpressed during aging. RNA-Seq data analysis identified 97 down-modulated DEG in the IGF-1 group as compared to the DsRed one. Interestingly, 12 of these DEG are commonly overexpressed during aging, and 9 out of 12 are expressed in microglia/macrophages and are involved in different processes that lead to neuroinflammation and/or neuronal loss. Finally, we observed that IGF-1 overexpression led to an improvement in motor functions. Although further studies are necessary, with the present results, we conclude that IGF-1 gene transfer is modifying both the pro-inflammatory environment and activation of microglia/macrophages in CPu. In this regard, IGF-1 gene transfer could counteract the neuroinflammatory effects associated with aging and improve motor functions in senile animals.

IGF1 Gene Therapy Reversed Cognitive Deficits and Restored Hippocampal Alterations After Chronic Spinal Cord Injury.

The hippocampus is implicated in the generation of memory and learning, processes which involve extensive neuroplasticity. The generation of hippocampal adult-born neurons is particularly regulated by glial cells of the neurogenic niche and the surrounding microenvironment. Interestingly, recent evidence has shown that spinal cord injury (SCI) in rodents leads to hippocampal neuroinflammation, neurogenesis reduction, and cognitive impairments. In this scenario, the aim of this work was to evaluate whether an adenoviral vector expressing IGF1 could reverse hippocampal alterations and cognitive deficits after chronic SCI. SCI caused neurogenesis reduction and impairments of both recognition and working memories. We also found that SCI increased the number of hypertrophic arginase-1 negative microglia concomitant with the decrease of the number of ramified surveillance microglia in the hilus, molecular layer, and subgranular zone of the dentate gyrus. RAd-IGF1 treatment restored neurogenesis and improved recognition and working memory impairments. In addition, RAd-IGF1 gene therapy modulated differentially hippocampal regions. In the hilus and molecular layer, IGF1 gene therapy recovered the number of surveillance microglia coincident with a reduction of hypertrophic microglia cell number. However, in the neurogenic niche, IGF1 reduced the number of ramified microglia and increased the number of hypertrophic microglia, which as a whole expressed arginase-1. In summary, RAd-IGF1 gene therapy might surge as a new therapeutic strategy for patients with hippocampal microglial alterations and cognitive deficits such as those with spinal cord injury and other neurodegenerative diseases.

Sex frailty differences in ageing mice: Neuropathologies and therapeutic projections.

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.

IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats.

Microglial cells become dystrophic with aging; this phenotypic alteration contributes to basal central nervous system (CNS) neuroinflammation being a risk factor for age related neurodegenerative diseases. In previous studies we have observed that insulin like growth factor 1 (IGF1) gene therapy is a feasible approach to target brain cells, and that is effective to modify inflammatory response in vitro and to ameliorate cognitive or motor deficits in vivo. Based on these findings, the main aim of the present study is to investigate the effect of IGF1 gene therapy on microglia distribution and morphology in the senile rat. We found that IGF1 therapy leads to a region-specific modification of aged microglia population.

Aldehyde dehydrogenase 2 in the spotlight: The link between mitochondria and neurodegeneration.

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.

The thymus-neuroendocrine axis: physiology, molecular biology, and therapeutic potential of the thymic peptide thymulin.

Thymulin is a thymic hormone exclusively produced by the thymic epithelial cells. It consists of a nonapeptide component coupled to the ion zinc, which confers biological activity to the molecule. After its discovery in the early 1970s, thymulin was characterized as a thymic hormone involved in several aspects of intrathymic and extrathymic T cell differentiation. Subsequently, it was demonstrated that thymulin production and secretion is strongly influenced by the neuroendocrine system. Conversely, a growing core of information, to be reviewed here, points to thymulin as a hypophysotropic peptide. In recent years, interest has arisen in the potential use of thymulin as a therapeutic agent. Thymulin was shown to possess anti-inflammatory and analgesic properties in the brain. Furthermore, an adenoviral vector harboring a synthetic gene for thymulin, stereotaxically injected in the rat brain, achieved a much longer expression than the adenovirally mediated expression in the brain of other genes, thus suggesting that an anti-inflammatory activity of thymulin prevents the immune system from destroying virus-transduced brain cells. Other studies suggest that thymulin gene therapy may also be a suitable therapeutic strategy to prevent some of the endocrine and metabolic alterations that typically appear in thymus-deficient animal models. The present article briefly reviews the literature on the physiology, molecular biology, and therapeutic potential of thymulin.