Neuroinflammation is an inflammatory response through which the brain immune cells eliminate pathogens, cell debris or misfolded proteins. As a defence mechanism, it is finalized to the preservation of the brain, however the prolonged inflammatory status leads to the onset of neurodegenerative disorders [1]. Oxidative stress is an imbalance between free radicals and antioxidants in favour of pro- oxidants. Given that both neuroinflammation and oxidative stress are implicated in the patho- genesis of neurodegenerative disorders, antioxidants and anti-inflammatory compounds may be useful for counteracting them. Vitamin C (Vit C) is known to have anti-inflammatory and antioxidant properties and, although its neuroprotective effects have been elucidated, the underlying molecular mechanisms remain unclear [2]. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase which acts as a potent driver of inflammation, rendering GSK3β inhibitors a promising target of anti-inflammatory research [3]. In this study, we have investigated the role of GSK3β inactivation in the context of Vit C neuroprotective effects by using a well-known 1-methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine (MPTP)-induced preclinical animal model of Parkinson’s disease (PD) and LPS-treated BV2 cells as alternative model system for activated primary microglia cultures. We found that Vit C regulates the inflammatory response up-regulating the expression of the anti-inflammatory cytokine IL-4 and down-regulating the pro-inflammatory cytokine IL-6 both in in vitro and in vivo models. In addition, the levels of superoxide dismutase 1 (SOD1) antioxidant enzyme were increased by Vit C in both models. In response to Vit C, GSK3β pro- tein was inactivated and p-p38 underwent an increase compared to control, suggesting that p-p38 may play a role in inactivating GSK3β. Moreover, Vit C is able to increase the cytosolic levels of β-catenin and consequently its nuclear translocation, giving a possible explanation to the anti-inflammatory and antioxidant functions of Vit C. Collectively, these results demonstrate that Vit C exhibits substantial neuroprotective effects through the modulation of GSK3β path- way, attenuating pro-inflammatory and up-regulating anti-inflammatory processes.
Neuroprotective effects of vitamin C: new insight about the GSK3β signaling pathway modulation
Melania Ruggiero;Antonia Cianciulli;Rosa Calvello;Maria Antonietta Panaro
2022-01-01
Abstract
Neuroinflammation is an inflammatory response through which the brain immune cells eliminate pathogens, cell debris or misfolded proteins. As a defence mechanism, it is finalized to the preservation of the brain, however the prolonged inflammatory status leads to the onset of neurodegenerative disorders [1]. Oxidative stress is an imbalance between free radicals and antioxidants in favour of pro- oxidants. Given that both neuroinflammation and oxidative stress are implicated in the patho- genesis of neurodegenerative disorders, antioxidants and anti-inflammatory compounds may be useful for counteracting them. Vitamin C (Vit C) is known to have anti-inflammatory and antioxidant properties and, although its neuroprotective effects have been elucidated, the underlying molecular mechanisms remain unclear [2]. Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase which acts as a potent driver of inflammation, rendering GSK3β inhibitors a promising target of anti-inflammatory research [3]. In this study, we have investigated the role of GSK3β inactivation in the context of Vit C neuroprotective effects by using a well-known 1-methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine (MPTP)-induced preclinical animal model of Parkinson’s disease (PD) and LPS-treated BV2 cells as alternative model system for activated primary microglia cultures. We found that Vit C regulates the inflammatory response up-regulating the expression of the anti-inflammatory cytokine IL-4 and down-regulating the pro-inflammatory cytokine IL-6 both in in vitro and in vivo models. In addition, the levels of superoxide dismutase 1 (SOD1) antioxidant enzyme were increased by Vit C in both models. In response to Vit C, GSK3β pro- tein was inactivated and p-p38 underwent an increase compared to control, suggesting that p-p38 may play a role in inactivating GSK3β. Moreover, Vit C is able to increase the cytosolic levels of β-catenin and consequently its nuclear translocation, giving a possible explanation to the anti-inflammatory and antioxidant functions of Vit C. Collectively, these results demonstrate that Vit C exhibits substantial neuroprotective effects through the modulation of GSK3β path- way, attenuating pro-inflammatory and up-regulating anti-inflammatory processes.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
