IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats

Lockhart, Eugenia Falomir; Dolcetti, Franco Juan Cruz; García‐Segura, Luis M.; Hereñú, Claudia Beatriz; Bellini, María José

doi:10.3389/fnagi.2019.00048

Cited by 21 publications

(21 citation statements)

References 43 publications

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“…All together, these results could indicate that normal working memory can be preserved long-term after injury if critical initial secondary injury mechanisms were prevented in brain structures critical to this cognitive function. This novel therapeutic approach could be beneficial from IGF-1 peripheral administration for many reasons: first, local over-expression can be maintained even after a month from a single administration ( Falomir-Lockhart et al, 2019 ); second, local over-expression may reduce systemic effects compared to peripheral administrations which may need massive doses in order to reach therapeutic CNS IGF-1 concentrations and lastly no doubts about treatment patient’s adherence, since administration must be performed during hospitalization, in a temporal window that guarantees the pharmacological effect.…”

Section: Discussionmentioning

confidence: 99%

Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury

et al. 2021

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Traumatic Brain Injury (TBI) remains a leading cause of morbidity and mortality in adults under 40 years old. Once primary injury occurs after TBI, neuroinflammation and oxidative stress (OS) are triggered, contributing to the development of many TBI-induced neurological deficits, and reducing the probability of critical trauma patients´ survival. Regardless the research investment on the development of anti-inflammatory and neuroprotective treatments, most pre-clinical studies have failed to report significant effects, probably because of the limited blood brain barrier permeability of no-steroidal or steroidal anti-inflammatory drugs. Lately, neurotrophic factors, such as the insulin-like growth factor 1 (IGF-1), are considered attractive therapeutic alternatives for diverse neurological pathologies, as they are neuromodulators linked to neuroprotection and anti-inflammatory effects. Considering this background, the aim of the present investigation is to test early IGF-1 gene therapy in both OS markers and cognitive deficits induced by TBI. Male Wistar rats were injected via Cisterna Magna with recombinant adenoviral vectors containing the IGF-1 gene cDNA 15 min post-TBI. Animals were sacrificed after 60 min, 24 h or 7 days to study the advanced oxidation protein products (AOPP) and malondialdehyde (MDA) levels, to recognize the protein oxidation damage and lipid peroxidation respectively, in the TBI neighboring brain areas. Cognitive deficits were assessed by evaluating working memory 7 days after TBI. The results reported significant increases of AOPP and MDA levels at 60 min, 24 h, and 7 days after TBI in the prefrontal cortex, motor cortex and hippocampus. In addition, at day 7, TBI also reduced working memory performance. Interestingly, AOPP, and MDA levels in the studied brain areas were significantly reduced after IGF-1 gene therapy that in turn prevented cognitive deficits, restoring TBI-animals working memory performance to similar values regarding control. In conclusion, early IGF-1 gene therapy could be considered a novel therapeutic approach to targeting neuroinflammation as well as to preventing some behavioral deficits related to TBI.

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Section: Discussionmentioning

confidence: 99%

Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury

et al. 2021

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“…Intranasal application of insulin (Chen et al, 2018; Freiherr et al, 2013; Guo et al, 2017) and a trophic factor enriched fraction of human plasma improved behavior and synaptic plasticity in AD models (Anitua et al, 2013). IGF1 is a potent neuroprotective peptide that promotes neuron survival and reduces neuroinflammation (Ashpole et al, 2015; Falomir‐Lockhart et al, 2019; Gomes et al, 2009). We have previously performed icv IGF1 gene therapy in the brain of senile rats, which displays spatial memory deficit.…”

Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor 1 gene transfer for sporadic Alzheimer's disease: New evidence for trophic factor mediated hippocampal neuronal and synaptic recovery‐based behavior improvement

et al. 2021

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Sporadic Alzheimer's disease (sAD) is the most prevalent neurodegenerative disorder with no cure. Patients typically suffer from cognitive impairment imprinted by irreversible neocortex and hippocampal degeneration with overt synaptic and neuron dysfunction. Insulin‐like growth factor 1 (IGF1) has proven to be a potent neuroprotective molecule in animal models of age‐related neurodegeneration. In this regard, adenoviral gene transfer aiming at IGF1 brain overexpression has been hitherto an underexplored approach for the sAD treatment. We postulated enhanced IGF1 signaling in the brain as a restorative means in the diseased brain to revert cognitive deficit and restore hippocampal function. We implemented recombinant adenovirus mediated intracerebroventricular IGF1 gene transfer on the streptozotocin (STZ) induced sAD rat model, using 3‐month‐old male Sprague Dawley rats. This approach enhanced IGF1 signaling in the hippocampus and dampened sAD phosphorylated Tau. We found a remarkable short‐term improvement in species‐typical behavior, recognition memory, spatial memory, and depressive‐like behavior. Histological analysis revealed a significant recovery of immature hippocampal neurons. We additionally recorded an increase in hippocampal microglial cells, which we suggest to exert anti‐inflammatory effects. Finally, we found decreased levels of pre‐ and postsynaptic proteins in the hippocampus of STZ animals. Interestingly, IGF1 gene transfer increased the levels of PSD95 and GAD65/67 synaptic markers, indicating that the treatment enhanced the synaptic plasticity. We conclude that exogenous activation of IGF1 signaling pathway, 1 week after intracerebroventricular STZ administration, protects hippocampal immature neurons, dampens phosphorylated Tau levels, improves synaptic function and therefore performs therapeutically on the sAD STZ model. Hence, this study provides strong evidence for the use of this trophic factor to treat AD and age‐related neurodegeneration.

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“…Although there are some limitations, such as immunogenic reactions and a lack of specificity of viral vectors, gene therapy has been applied with positive outcomes in neurological diseases, including MS 82 . Insulin-like growth factor 1 (IGF1) gene therapy could target microglia, modify the inflammatory response and improve cognitive or motor deficits 83 . Therefore, gene therapeutic approaches might be a promising choice to partially modulate the progression of NMOSD by targeting microglial activation.…”

Section: Prospects and Potential Applicationsmentioning

confidence: 99%

The role and mechanisms of Microglia in Neuromyelitis Optica Spectrum Disorders

Li¹,

Liu²,

Tan³

et al. 2021

Int. J. Med. Sci.

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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune neurological disease that can cause blindness and disability. As the major mediators in the central nervous system, microglia plays key roles in immunological regulation in neuroinflammatory diseases, including NMOSD. Microglia can be activated by interleukin (IL)-6 and type I interferons (IFN-Is) during NMOSD, leading to signal transducer and activator of transcription (STAT) activation. Moreover, complement C3a secreted from activated astrocytes may induce the secretion of complement C1q, inflammatory cytokines and progranulin (PGRN) by microglia, facilitating injury to microglia, neurons, astrocytes and oligodendrocytes in an autocrine or paracrine manner. These processes involving activated microglia ultimately promote the pathological course of NMOSD. In this review, recent research progress on the roles of microglia in NMOSD pathogenesis is summarized, and the mechanisms of microglial activation and microglialmediated inflammation, and the potential research prospects associated with microglial activation are also discussed.

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IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats

Cited by 21 publications

References 43 publications

Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury

Early IGF-1 Gene Therapy Prevented Oxidative Stress and Cognitive Deficits Induced by Traumatic Brain Injury

Insulin‐like growth factor 1 gene transfer for sporadic Alzheimer's disease: New evidence for trophic factor mediated hippocampal neuronal and synaptic recovery‐based behavior improvement

The role and mechanisms of Microglia in Neuromyelitis Optica Spectrum Disorders

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