Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction

Hereñú, Claudia Beatriz; Cristina, Carolina; Rimoldi, Omar J.; Becú-Villalobos, Damasia; Cambiaggi, Vanina Laura; Portiansky, Enrique Leo; Goya, Rodolfo G.

doi:10.1038/sj.gt.3302870

Cited by 55 publications

(52 citation statements)

References 43 publications

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“…The majority of pituitary tumors in females are prolactinomas that result from loss of tuberoinfundibular dopamine levels within the hypothalamus. The fact that IGF-1 replacement has been demonstrated to preserve the function of these neurons, restore dopamine levels, and suppress prolactin suggests that this effect is not directly related to IGF-1 deficiency but mediated through other indirect mechanisms (Herenu et al 2007). …”

Section: Discussionmentioning

confidence: 99%

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

et al. 2017

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Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.

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Section: Discussionmentioning

confidence: 99%

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

et al. 2017

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“…In effect, it is well-established that in the female rat, the hypothalamic dopaminergic (DA) neurons which exert a tonic inhibitory control on prolactin secretion, become dysfunctional with age [67]. A significant reversal of chronic hyperprolactinemia and hypothalamic DA neuron dysfunction was achieved by neurotrophic factor gene therapy in the hypothalamus of aged female rats [68,69]. In these studies the therapeutic viral vectors were injected into the hypothalamic parenchyma.…”

Section: Neurological Diseasesmentioning

confidence: 99%

Magnetic Field-Assisted Gene Delivery: Achievements and Therapeutic Potential

Schwerdt

Goya²,

Calatayud³

et al. 2012

CGT

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The discovery in the early 2000's that magnetic nanoparticles (MNPs) complexed to nonviral or viral vectors can, in the presence of an external magnetic field, greatly enhance gene transfer into cells has raised much interest. This technique, called magnetofection, was initially developed mainly to improve gene transfer in cell cultures, a simpler and more easily controllable scenario than in vivo models. These studies provided evidence for some unique capabilities of magnetofection. Progressively, the interest in magnetofection expanded to its application in animal models and led to the association of this technique with another technology, magnetic drug targeting (MDT). This combination offers the possibility to develop more efficient and less invasive gene therapy strategies for a number of major pathologies like cancer, neurodegeneration and myocardial infarction. The goal of MDT is to concentrate MNPs functionalized with therapeutic drugs, in target areas of the body by means of properly focused external magnetic fields. The availability of stable, nontoxic MNP-gene vector complexes now offers the opportunity to develop magnetic gene targeting (MGT), a variant of MDT in which the gene coding for a therapeutic molecule, rather than the molecule itself, is delivered to a therapeutic target area in the body. This article will first outline the principle of magnetofection, subsequently describing the properties of the magnetic fields and MNPs used in this technique. Next, it will review the results achieved by magnetofection in cell cultures. Last, the potential of MGT for implementing minimally invasive gene therapy will be discussed.

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“…Morphometric analysis revealed a significant increase in the total number of tyrosine hydroxylase (TH) positive cells in the hypothalamus of experimental as compared with control senile animals. 26 These results suggested, although did not prove, that IGF-I may have a neurogenic action on hypothalamic DA neuron populations in senile animals. Interestingly, IGF-I gene therapy did not affect DA neuron population in the hypothalamus of young rats.…”

Section: Gene Therapy For Igf-imentioning

confidence: 67%

Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging

et al. 2016

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In rats, learning and memory performance decline during normal aging, which is paralleled by a severe reduction of the levels of neurogenesis in the hippocampal dentate gyrus (DG). A promising therapeutic strategy to restore neurogenesis in the hippocampus of old rats and their spatial memory involves the use of insulin-like growth factor-I (IGF-I). The peptide exerts pleiotropic effects in the brain, regulating multiple cellular processes. Thus, 4-week intracerebroventricular (ICV) perfusion of IGF-I significantly restored spatial memory and hippocampal neurogenesis in old male rats. Similar results were achieved by ICV IGF-I gene therapy in aging female rats. Thus, the treatment seemed to increase the number of immature neurons in the DG of 28 mo old rats, which was paralleled by an increase in the accuracy of the animals to remember specific patterns, which is known as pattern separation memory. The DG is thought to be the main hippocampal structure involved in pattern separation memory and there is evidence that the level of neurogenesis in the DG is directly related to pattern separation performance in rodents. Summing up, IGF-I emerges as a promising restorative molecule for increasing hippocampal neurogenesis and memory accuracy in aged individuals and possibly, in neurodegenerative pathologies.

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Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction

Cited by 55 publications

References 43 publications

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan

Magnetic Field-Assisted Gene Delivery: Achievements and Therapeutic Potential

Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging

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