Pentoxifylline attenuates TNF-α protein levels and brain edema following temporary focal cerebral ischemia in rats

Cerebral edema is the most common cause of neurological deterioration and mortality during acute ischemic stroke. Despite the clinical importance of cerebral ischemia, the underlying mechanisms remain poorly understood. Recent studies suggest a role for TNF-α in the brain edema formation. To further investigate whether TNF-α would play a role in brain edema formation, we examined the effects of pentoxifylline (PTX, an inhibitor of TNF-α synthesis) on the brain edema and TNF-α levels in a model of transient focal cerebral ischemia. The right middle cerebral artery (MCA) of rats was occluded for 60 min using the intraluminal filament method. The animals received PTX (60 mg/kg) immediately, 1, 3, or 6 h post-ischemic induction. Twenty-four hours after induction of ischemic injury, permeability of the blood–brain barrier (BBB) and brain edema were determined by in situ brain perfusion of Evans Blue (EB) and wet-to-dry weight ratio, respectively. TNF-α protein levels in ischemic cortex were also measured at 1, 4, and 24 h after the beginning of an ischemic stroke by using an enzyme-linked immunosorbent assay method. The administration of PTX up to 6 h after occlusion of the MCA significantly reduced the brain edema. Moreover, PTX significantly reduced the concentration of TNF-α in ischemic brain cortex up to 4 h post-transient focal stroke (P < 0.002). Finally, treatment by PTX led to a significant decrease in EB extravasations (P < 0.001). Our data demonstrate that PTX administration up to 6 h after ischemia can reduce brain edema in a model of transient focal cerebral ischemia. The beneficial effects of PTX may be mediated, at least in part, through a decline in TNF-α production and BBB breakdown.

Research Highlights
► Synthesis of TNF-α enhances during acute phase of focal stroke.
► Increase of production TNF-α causes blood–brain barrier (BBB) disruption and brain edema.
► Blockage of synthesis TNF-α by pentoxifylline attenuated BBB disruption and brain edema.