Reactivity of microglia and astrocytes after an excitotoxic injury induced by kainic acid in the rat spinal cord

Zanuzzi, Carolina Natalia; Nishida, Fabián; Sisti, María Susana; Barbeito, Claudio Gustavo; Portiansky, Enrique Leo

doi:10.1016/j.tice.2018.11.007

Cited by 17 publications

(10 citation statements)

References 48 publications

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“…For cell counting, ImagePro Plus (V6.3, Media Cybernetics, USA) image analyzer was used. After color segmentation of digital images, cells that met neuronal (Nishida et al., 2015) or glial (Zanuzzi et al, 2019) parameters were included in the counting.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous report, using the intracerebroventricular (ICV) route, we showed that recombinant IGF‐1 gene adenovector injected into the fourth ventricle reached the ependymal cells and improved motor performance of 30‐month‐old rats (Nishida et al., 2011). In the recent years, we developed an animal excitotoxic SCI model showing functional and histopathological changes induced by the intraparenchymal injection of kainic acid (KA) into the C5 segment of the spinal cord (Nishida, Zanuzzi, Márquez, Barbeito, & Portiansky, 2014; Nishida, Zanuzzi, Martínez, Barbeito, & Portiansky, 2015; Sisti, Zanuzzi, Nishida, Cantet, & Portiansky, 2018; Zanuzzi et al, 2019). As it is known that besides the ICV route the intracisternal (IC) route is an alternative and less invasive way for gene therapy delivery to treat different SNC diseases (Bell et al., 2015; Hinderer et al., 2018; Kondagari et al., 2015; Markmann et al., 2018; Spinelli et al., 2019), here we propose the latter route to abrogate or at least reduce the structural and behavioral damage induced by KA at the spinal cord.…”

Section: Introductionmentioning

confidence: 99%

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Intracisternal IGF‐1 gene therapy abrogates kainic acid‐induced excitotoxic damage of the rat spinal cord

Nishida

Zanuzzi

Sisti

et al. 2020

Eur J of Neuroscience

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Development of alternative therapies for treating functional deficits after different neurological damages is a challenge in neuroscience. Insulin-like growth factor-1 (IGF-1) is a potent neurotrophic factor exerting neuroprotective actions in brain and spinal cord. It is used to prevent or treat injuries of the central nervous system using different administration routes in different animal models. In this study, we evaluated whether intracisternal (IC) route for IGF-1 gene therapy may abrogate or at least reduce the structural and behavioral damages induced by the intraparenchymal injection of kainic acid (KA) into the rat spinal cord. Experimental (Rad-IGF-1) and control (Rad-DsRed-KA) rats were evaluated using a battery of motor and sensory tests before the injection of the recombinant adenovector (day −3), before KA injection (day 0) and at every post-injection (pi) time point (days 1, 2, 3 and 7 pi). Histopathological changes and neuronal and glial counting were assessed. Pretreatment using IC delivery of RAd-IGF-1 improved animal's general condition and motor and sensory functions as compared to Rad-DsRed-KA-injected rats. Besides, IC Rad-IGF-1 therapy abrogated later spinal cord damage and reduced the glial response induced by KA as observed in Rad-DsRed-KA rats. We conclude that the IC route for delivering RAd-IGF-1 prevents KA-induced excitotoxicity in the spinal cord. K E Y W O R D S adenoviral gene therapy, intracisternal route, neurotoxicity, neurotrophic factor 3340 | NISHIDA et Al. How to cite this article: Nishida F, Zanuzzi CN, Sisti MS, et al. Intracisternal IGF-1 gene therapy abrogates kainic acid-induced excitotoxic damage of the rat spinal cord.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intracisternal IGF‐1 gene therapy abrogates kainic acid‐induced excitotoxic damage of the rat spinal cord

Nishida

Zanuzzi

Sisti

et al. 2020

Eur J of Neuroscience

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“…For astrocytes estimation as an indicator of inflammatory process, GFAP immunostained area was considered. For that purpose, color segmentation to detect positively stained cells inside a ROI (as previously defined) was applied and its area was calculated [16,24]. In all cases, estimation of immunostaining was carried out in sections located up to 500 μm in front of and behind the injection site.…”

Section: Morphometrymentioning

confidence: 99%

Lidocaine protects neurons of the spinal cord in an excitotoxicity model

Sisti

Nishida

Zanuzzi

et al. 2019

Neuroscience Letters

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“…The latter can be further divided into three categories: N-methyl D-aspartate receptor (NMDAR), α-amino-3 hydroxy-5 methyl-4-isoxazole receptor (AMPAR), and KA [10,31] . Recent studies have found that when the concentration of extracellular glutamate increases, glycoproteins on the microglia membrane can rapidly transport glutamate in synaptic space, which is of great signi cance to prevent excitatory toxicity of glutamate, which therefore may be therapeutic targets for neurodegenerative diseases [32][33][34] . However, it is not clear what the reaction mechanisms of microglia regular by KA during the secondary nerve injury of diseases.…”

Section: Introductionmentioning

confidence: 99%

Regulatory effect of kainic acid on microglia in different inflammatory states

Wang

Zhou

Zhang

et al. 2021

Preprint

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BackgroundNerve injury is a crucial factor in the development of various neurodegenerative diseases in the central nervous system (CNS). It was demonstrated that neuroinflammatory response mediated by reactive microglia with different activated phenotypes plays an important role in different stages of nerve injury. Nerve injury leads to glutamate spillover, which also causes damage surrounding neurons, neurotoxic reactions, and neuroinflammatory so that glutamate spillover is one of the important mechanisms of nerve injury, among which the kainic acid (KA) signal pathway of glutamate ionotropic receptor induces neurotoxicity most significantly. In addition to inducing nerve damage, KA has been found to regulate microglia, further to induce the functional response of microglia.MethodsIn the present study, we constructed the different phenotypes of microglia stimulated with KA to activate the KA receptor signal pathway of microglia. The activity of microglia, Nitric oxide (NO) levels, lactate dehydrogenase (LDH) production, and cytokine levels were further investigated to explore the different immune response effects of different phenotypes of microglia during the KA stimulation and their role in disease development.ResultsOur results show that after 24 hours (h) of cell culture, KA activation causes a large consumption of pro-inflammatory microglia phenotype, the release of NO and pro-inflammatory cytokines decreased, and the anti-inflammatory cytokines increased. The resting microglia and anti-inflammatory microglia phenotype stimulated with KA are well tolerated after activation. After 48 h of culture, during the KA stimulation, the cell survival rate increased after activation of the pro-inflammatory microglia, and the secretion of NO, pro-inflammatory, and anti-inflammatory cytokines increased. The activation of resting microglia and anti-inflammatory microglia leads to decreased cell survival and decreased secretion of pro-inflammatory and anti-inflammatory cytokines. After 72 h of culture, the cell survival rate and NO release decreased after KA stimulation of the pro-inflammatory microglia. The anti-inflammatory microglia treated by KA increased cell activity and survival rate after activation.ConclusionsOur results may reveal the situation for the massive consumption of microglia after the KA stimulation in the early phase of nerve injury, at the same time, it was revealed that anti-inflammatory microglia not only had a high survival rate in the high concentration of glutamate but also could produce anti-inflammatory cytokines and play a protective role. It may provide a novel strategy for the treatment and recovery, suggest a scheme for the protection of microglia and resistance to secondary injury.

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Reactivity of microglia and astrocytes after an excitotoxic injury induced by kainic acid in the rat spinal cord

Cited by 17 publications

References 48 publications

Intracisternal IGF‐1 gene therapy abrogates kainic acid‐induced excitotoxic damage of the rat spinal cord

Intracisternal IGF‐1 gene therapy abrogates kainic acid‐induced excitotoxic damage of the rat spinal cord

Lidocaine protects neurons of the spinal cord in an excitotoxicity model

Regulatory effect of kainic acid on microglia in different inflammatory states

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