Pentoxifylline Attenuates Hypoxic-Ischemic Brain Injury in Immature Rats

Abstract

Inflammatory mediators are implicated in the pathogenesis of ischemic injury in immature brain. The phosphodiesterase inhibitor pentoxifylline inhibits production of tumor necrosis factor-alpha and platelet-activating factor. We hypothesized that pentoxifylline treatment would attenuate hypoxic-ischemic brain injury in immature rats. Seven-day-old rats (n = 79) underwent right carotid ligation, followed by hypoxia (FiO2 = 0.08). Rats received pentoxifylline immediately before and again after hypoxia (two doses, 25-150 mg/kg/dose, n = 34), or vehicle (n = 27). In separate experiments, rats received pentoxifylline treatment (40 mg/kg/dose, n = 8), or vehicle (n = 10) immediately and again 3 h after hypoxia-ischemia. Severity of injury was assessed 5 d later by visual evaluation of ipsilateral hemisphere infarction and by measurement of bilateral hemispheric cross-sectional areas. Pentoxifylline pretreatment reduced the incidence of liquefactive cerebral infarction, from 75% in controls to 10% with pentoxifylline, 40 mg/kg/dose (p<0.001, chi2 trend test). Quantification of hemispheric areas confirmed these findings. In contrast, posthypoxic-ischemic treatment with pentoxifylline resulted in only a modest reduction in cortical damage, without an overall reduction in incidence of infarction. Phosphodiesterase inhibition may be an effective strategy to use to decrease the severity of neonatal hypoxic-ischemic brain injury. Pretreatment regimens could be clinically relevant in settings in which an increased risk of cerebral ischemia can be anticipated, such as in infants undergoing surgery to correct congenital heart disease.

Neonatal encephalopathy in the term infant: Neuroimaging and inflammatory cytokines

“…Overexpression of IL-9 by a transgenic mouse, or exogenous addition of IL-1␣, IL-6, IL-9, and TNF␣ increased CNS injury by ibotenate, a glutamate analogue [Dommergues et al, 2000]. Using a TNF-␣ inhibitor, pentoxifylline, a decrease in CNS injury was seen in a hypoxia-ischemia model [Eun et al, 2000]. Cytokines are toxic in vitro [Jeohn et al, 1998] to neurons and inhibit oligodendrocyte development as well [Merrill, 1992].…”

Timing of Neutrophil Depletion Influences Long-Term Neuroprotection in Neonatal Rat Hypoxic-Ischemic Brain Injury

“…Neutrophil-induced microvascular dysfunction will be even more likely if hypotension and cerebral hypoperfusion occur in the very susceptible sick premature infant. Accordingly, brain injury might be reduced by approaches that maintain cerebral perfusion (66), that reduce the effect of circulating inflammatory cytokines, and that reduce neutrophil-endothelial activation/adhesion (67).…”

Pentoxifylline Prevents Spontaneous Brain Ischemia in Stroke-Prone Rats

“…Studies of the anti-inflammatory effects of PTX in vivo have focused attention on tissue injury after ischemia. Thus, in vivo PTX treatment reduced ischemia-reperfusion injury in the lung (Thabut et al, 2001), intestine (Sener et al, 2001), liver (Iwamoto et al, 2002), kidney (Kim et al, 2001), spinal cord (Savas et al, 2002), and brain of different animal species including rats, mice, and dogs (Toung et al, 1994;Sirin et al, 1998;Eun et al, 2000). Inflammatory processes accompany tissue injury regardless of the organ system involved, and chronic inflammation may predispose to ischemia in peripheral organs and to brain damage (Lindsberg and Grau, 2003).…”