Alleviation of Oxidative Damage and Involvement of Nrf2‐ARE Pathway in Mesodopaminergic System and Hippocampus of Status Epilepticus Rats Pretreated by Intranasal Pentoxifylline

Abstract

The current studies were aimed at evaluating the efficacy of intranasal pentoxifylline (Ptx) pretreatment in protecting mesodopaminergic system and hippocampus from oxidative damage of lithium-pilocarpine induced status epilepticus (SE) and the involvement of nuclear factor erythroid 2-related factor 2- (Nrf2-) antioxidant response elements pathway. Pentoxifylline was administered to rats intranasally or intraperitoneally 30 minutes before inducing SE. Our results showed the impaired visuospatial memory, the defected mesodopaminergic system, and the oxidative damage and the transient activation of Nrf2 in SE rats. The transient activation of Nrf2 in SE rats was enhanced by Ptx pretreatment, which was followed by the upregulation of heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Ptx pretreatment to SE rats significantly suppressed the epileptic seizures, decreased the levels of lipid peroxide and malondialdehyde, and elevated the ratio of reduced glutathione/oxidized glutathione. Compared with intraperitoneal injection, intranasal Ptx delivery completely restored the visuospatial memory and the activity of mesodopaminergic system in SE rats. Intranasal administration of Ptx may hopefully become a noninvasive, painless, and easily administered option for epileptic patients.

Pentoxifylline prevents epileptic seizure via modulating HMGB1/RAGE/TLR4 signalling pathway and improves memory in pentylenetetrazol kindling rats

“…The activated nerve/glial cells stimulate HMGB1‐TLR4 signalling, which triggers Ca 2+ release, resulting in increases neuronal excitotoxicity leading to frequent seizures, and precipitate to neuronal damage. Based on these mechanisms, HMGB1‐TLR4 network signalling plays a fundamental role in epileptic seizures initiation and progression 28,31 . The current data were matched with the previous studies, 2,30 which indicated the relationship between HMGB1‐TLR4 signalling pathway and epileptogenesis, since it revealed upregulated pro‐inflammatory cytokines, HMGB1 and TLR4, which hindered by PTX treatment.…”

“…Pentoxifylline is broadly utilized therapeutically to enhance the circulation in peripheral vascular diseases 26 . Several studies have reported PTX evoked repression in HMGB1 production with apparent reduction in its downstream inflammatory/oxidative networks, mediated by TLR4 leading to subsequent decreased oxidative stress and improved pathophysiological conditions in the chronic inflammatory diseases 17,18,27,28 …”

“…The non‐specific inhibitor of phosphodiesterase, pentoxifylline (PTX), has a well validated immune modulatory and anti‐inflammatory efficacy via suppression of the TLR4/NF‐κB network signalling pathway 12‐15 . Moreover, PTX has a potential antioxidant capacity mostly via nuclear erythroid 2‐related factor 2 (Nrf2) activation, consequently upregulated expression of several antioxidant enzymes 16,17 . Several studies showed the protective effect of PTX against several neurobehavioral disorders such as ischaemic models of brain injury through several mechanisms including enhancement of cerebral vascular circulation 13,18 .…”

Pentoxifylline Enhances Antioxidative Capability and Promotes Mitochondrial Biogenesis in D‐Galactose‐Induced Aging Mice by Increasing Nrf2 and PGC‐1α through the cAMP‐CREB Pathway

“…Pentoxifylline (PTX), a methylxanthine derivative, has been applied clinically for the treatment of peripheral vascular diseases and cerebrovascular diseases [21]. Furthermore, it was reported that PTX has ameliorative effects on aging or other pathological processes, such as improving behavioral deficits and anti-inflammatory activity, restoring dopaminergic neurochemical levels and antioxidant activity, and ameliorating mitochondrial function [22][23][24][25]. These findings are also supported by our earlier research on the antiaging effects of PTX in aged rats, in which we found that the beneficial function might be related to Nrf2 activation [22].…”

Epilepsy Disease and Nose-to-Brain Delivery of Polymeric Nanoparticles: An Overview

“…Compared with intraperitoneal injection, IN pentoxifylline delivery completely restored the visuospatial memory and the activity of the mesodopaminergic system in status epilepticus rats. The findings obtained suggest that IN administration of pentoxifylline could effectively protect cells from oxidative damage in status epilepticus and may hopefully become a non-invasive, painless, and easily administered option for epileptic patients [62].…”