Abstract
Several studies have reported a relation between increased pro-inflammatory mediators such as TNF-α and apoptosis in neurodegenerative diseases such as Alzheimer’s disease (AD). It is known that lipopoly-saccharide (LPS) treatment induces neuroinflammation and memory deterioration, and it has been reported that LPS induces apoptosis mostly through the production of TNF-α. Pentoxifylline (PTX), is a vascular protective agent and a potent TNF-alpha inhibitor. However, the molecular neuroprotective mechanisms of PTX against LPS-induced neurotoxicity have not been well studied. In this study, we investigated the direct protective effect of PTX against LPS-induced toxicity in Rat pheochromocytoma (PC12) cell line. The results showed that a pretreatment with PTX prior exposure to LPS signifycantly decreased LPS-induced cell death. Mechanisms study showed that PTX has the potential to inhibit pro-inflammatory and pro-apoptotic pathways via the suppression of TNF-α and a caspase-dependent pathway in neuronal PC12 cells. This is the first study to report the anti-inflammatory and anti-apoptotic effects of PTX via inhibition of TNF-α and a caspase-dependent pathway in neuronal PC12 cells. Altogether, these observations indicate that PTX is capable of promoting neuroprotective effects, meanwhile also present some insights into the potential signaling pathways that are involved. Thus, these findings support the potential for PTX to be investigated as a potential agent for the treatment of neurodegenerative diseases such as AD.
Highlights
Alzheimer’s disease (AD) is an irreversible and progressive disorder affecting regions of the brain that control memory and cognitive functions
PC12 cells were treated as follows: For MTT assay, vehicle, LPS, Pentoxifylline (PTX)
Increasing genetic and clinical evidence supports that an excess of TNF-α plays a central role in neurodegeneration [39,40]
Summary
Alzheimer’s disease (AD) is an irreversible and progressive disorder affecting regions of the brain that control memory and cognitive functions. Studies have reported that a direct injection of LPS to the brain leads to neuronal death in the hippocampus [12]. This may be due to the presence of inflammatory factors as LPS administration to the brain in rodents induces chronic neuroinflammation associated with impaired hippocampal-dependent spatial cognitive function [13,14,15]. In addition to its ability to improve microcirculation, PTX has potent anti-TNF-α action [24] which have prompted investigations into its potential efficacy in disease states such as AD, where TNF-α levels are elevated and may intimately be associated with neuronal death [21,22]. The present result showed that PTX exerts its neuroprotection probably via the inhibition of TNF-α expression and a caspase-dependent apoptotic pathway
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