Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor

Abstract

We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective. However, the effect of PTx on VEGF has never been studied. We investigated whether PTx modulates neuronal VEGF expression and how it affects the pathogenesis of EAE. EAE was induced by injecting myelin oligodendrocyte glycoprotein 35-55 peptides with adjuvants into C57BL/6 mice. Clinical scores of EAE were evaluated daily for 19 days. Brain and spinal cord samples were collected and assessed for inflammation and demyelination. VEGF, NeuN for neurons, and Caspase-3 for apoptosis were stained for localization using immunohistochemistry techniques, followed by western blot analysis for quantification. Primary neurons were cultured to assess the direct effect of PTx on neuronal VEGF expression. PTx treatment increases neuronal VEGF expression by up to ∼75% in vitro and ∼60% in vivo, preventing neurons from apoptosis. This leads to resolution in inflammation and remyelination and amendment in motor deficits. Our findings suggest that upregulation of endogenous neuronal VEGF by PTx protects motor deficits in EAE and it is a potential therapeutic option for multiple sclerosis.

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

“…PTx treatment rescued cells from glutamate toxicity. PTx itself did not compromise the neuronal survival, which is consistent with our previous report on the experimental autoimmune encephalomyelopathy model of multiple sclerosis (Yin et al 2010;Tang et al 2013).…”

“…In our previous studies (Tang et al . ; Yin et al . ), we tested different doses of PTx, including 100, 200, 400 and 1000 ng; and different route of administration including intracerebroventricular, intravenous, and i.p.…”

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

“…In a stroke model, exogenous VEGF administration increases neurogenesis of the SVZ, only after 28 days, without concomitant angiogenesis, demonstrating that a specific VEGF isoform could protect neurons independently of the endothelial cell influence [231]. In the EAE model, despite several reports of an improved clinical score after early VEGF inhibition, one study [232] demonstrated that pertussis toxin stimulated VEGF expression and that VEGF neuroprotection could be responsible for milder disease. VEGF may have different effects in different cell types depending on different splice variants [233].…”

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

“…In a stroke model, exogenous VEGF administration increases neurogenesis of the SVZ, only after 28 days, without concomitant angiogenesis, demonstrating that a specific VEGF isoform could protect neurons independently of the endothelial cell influence [231]. In the EAE model, despite several reports of an improved clinical score after early VEGF inhibition, one study [232] demonstrated that pertussis toxin stimulated VEGF expression and that VEGF neuroprotection could Fingolimod Gilenya [210][211][212] Glatiramer acetate Copaxone [206,207] Interferon β-1a Avonex, Rebif [84,204,205] Interferon β-1b Betaferon, Extavia Mitoxantrone Novantrone [216] Natalizumab Tysabri [208,209] Teriflunomide Aubagio Only indirect evidence derived from antilymphocytes activity be responsible for milder disease. VEGF may have different effects in different cell types depending on different splice variants [233].…”