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Brain Res Bull. 2019 Jan;144:233-245. doi: 10.1016/j.brainresbull.2018.11.013. Epub 2018 Nov 22.

Effect of dimethyl fumarate on neuroinflammation and apoptosis in pentylenetetrazol kindling model in rats.

Author information

1
Department of Pharmacology, Post Graduate Institute of Medical Education & Research, 160012, Chandigarh, India.
2
Department of Pharmacology, Post Graduate Institute of Medical Education & Research, 160012, Chandigarh, India. Electronic address: lekhasaha@rediffmail.com.
3
Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, 160012, Chandigarh, India.

Abstract

OBJECTIVE:

Role of apoptosis and neuroinflammation have been well established in the pathogenesis of epilepsy. It has been reported that the activation of nuclear factor-erythroid 2-related factor-2 (Nrf2) contributes to the attenuation of inflammation by inhibiting nuclear factor-kB (NF-kB) pathway. Therefore, the present study was designed to evaluate anti-inflammatory and anti-apoptotic role of dimethyl fumarate (DMF), an activator of Nrf2, in chemical kindling model in rats.

METHODS:

Chemical kindling model was established in Wistar rats by intraperitoneal (i.p.) administration of pentylenetetrazole (PTZ). Animals were treated with DMF (60 mg/kg) to activate the Nrf2 antioxidant response element (ARE) pathway. The animals were assessed for seizure score, neuronal damage and inflammatory cytokines levels (IL-1β, IL-6 and TNF-α) in hippocampus. The mRNA levels of various genes (Nrf2, HO-1, NQO1, Bcl2, Bax, Caspase 3, NF-kB, IL-6, IL-1β and TNF-α) were quantified by real-time PCR. The expression of anti-oxidative (Nrf2), apoptotic (Bax, Bcl2) and inflammatory (NF-kB) proteins were analysed by western blot. Immunohistochemistry (Bax) and electron microscopy were done to assess apoptosis.

RESULTS:

The results showed reduction in the seizure score, percentage of kindled rats and neurological damage score in DMF treated rats. Pro-inflammatory cytokines concentrations were also decreased by DMF treatment. DMF downregulated the expression of inflammatory (NF-kB) and apoptotic (Bax, Caspase-3) genes and protein. DMF treatment increased the gene expression of Nrf2, HO-1, NQO1, Bcl-2 and protein expression of Nrf2 and Bcl2.

CONCLUSION:

DMF demonstrated anti-apoptotic, anti-inflammatory and anti-oxidative effect in hippocampus, which might be regulated by increased level of antioxidant response elements.

KEYWORDS:

Apoptosis; Dimethyl fumarate; Nuclear factor-erythroid 2-related factor-2 (Nrf2); Nuclear factor-kB (NF-kB); Pentylenetetrazol chemical kindling model

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