Recombinant Human Erythropoietin Prevents the Death of Mice during Cerebral Malaria

Abstract

Cerebral involvement during malaria is a complication that leads to seizure, coma, and death. The effect of new neuroprotective therapies has not yet been investigated, although cerebral malaria shares some features with neurological stroke. Erythropoietin (EPO) is one of the more promising drugs in this area. We measured the effect of EPO on the survival of mice infected with Plasmodium berghei ANKA and demonstrated that inoculations of recombinant human EPO at the beginning of the clinical manifestations of cerebral malaria protect >90% of mice from death. This drug has no effect on the course of parasitemia. The effect of EPO was not related to either the inhibition of apoptosis in the brain or the regulation of the increase and decrease of nitric oxide production in the brain and blood, respectively. Tumor necrosis factor-alpha and interferon-gamma mRNA overexpression was inhibited by EPO, and treated mice had fewer brain hemorrhages. EPO has been used in patients with chronic diseases for years, and more recently it has been used to treat acute ischemic stroke. The data presented here provide the first evidence indicating that this cytokine could be useful for the symptomatic prevention of mortality during the acute stage of cerebral malaria.

Protection against cerebral malaria by the low-molecular-weight thiol pantethine

“…Several compounds have been shown to protect against CM in the mouse, the steroid dexamethasone (42), which, however, proved deleterious in patients (43), anti-CD41 antibody (44), recombinant human EPO (45), and recombinant human IFN-␣ (46). The antioxidant N-acetylcysteine has been tested in patients with some success but shows hepatic toxicity (47,48).…”

Therapeutic Potential of Erythropoietin and its Structural or Functional Variants in the Nervous System

“…33,67,[91][92][93][94][95][96] Neuronal damage associated with cerebral malaria and radiosurgically-induced brain injury in mice can also be reduced by EPO and CEPO. [97][98][99] Translational relevance of these data is emphasized by a recent clinical study demonstrating that high plasma levels of EPO are associated with reduced risk of neurological sequelae in children with cerebral malaria. 100 Beneficial effects of both EPO and its nonhematopoietic derivatives and mimetics have been described in models of peripheral axonal nerve injury, injury-induced Wallerian degeneration, diabetic, and HIV-associated neuropathy.…”

“…41,[101][102][103][104][105] In these conditions, the anti-cytokine, antiapoptotic, anti-oxidative, and trophic effects on both neurons and oligodendrocyte progenitor cells are likely to reduce inflammation and preserve myelination and neuronal function. 33,67,[91][92][93][94][95][96][97][98]102,103 The initial observation by Grimm et al 106 of a potent neuroprotective effect of EPO in light-induced retinal degeneration has been confirmed in many other models of retinal disease in which EPO derivatives are in consideration for clinical use. 7,106 -109 Here, a local intravitreal administration has been proposed to avoid neovascularization and angiogenesis after systemic EPO therapy.…”

Erythropoietin and Oxidative Stress

“…In cells that involve the brain or the retina, EPO can prevent injury from hypoxic ischemia , Chong, et al, 2002b, Liu, et al, 2006, Meloni, et al, 2006, Wei, et al, 2006, Yu, et al, 2005, excitotoxicity (Montero, et al, 2007, Yamasaki, et al, 2005, infection (Kaiser, et al, 2006), free radical exposure , Chong, et al., 2003e, Yamasaki, et al, 2005, staurosporine (Pregi, et al, 2006), and dopaminergic cell injury (Demers, et al, 2005, McLeod, et al, 2006. In addition, administration of EPO also represents a viable option for the prevention of retinal cell injury during glaucoma (Tsai, et al, 2007).…”