VOL. 5, No. 1/2, July 2009

I. Karimzadeh, et al. [2009] Med. Hypotheses Res. 5: 79‒91.

Erythropoietin as a Neuroprotectant: Does Phenytoin
Exert its Neuroprotective Functions Through
Stimulation of Erythropoietin Production?

Iman Karimzadeh, Soha Namazi* and Ghazal Vessal

Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

Abstract. Neuropathic pain is caused by various central and peripheral nervous system
disorders. Sodium channel up-regulation, γ-amino butyric acid down-regulation, nerve
demyelination and sympathetic-somatosensory crosstalk are considered as important
pathophysiological mechanisms for neuropathic pain. Pharmacotherapy is currently the
mainstay of neuropathic pain treatment. Phenytoin, a classical anticonvulsant, has been
shown to provide neuroprotection through sodium and calcium channel blockade and
inhibition of glutamate release and glutamate receptors. On the other hand, it has been
shown that erythropoietin, the principal regulator of erythropoiesis, has important non-
hematopoietic actions such as neurodevelopment and neuroprotection. In this paper, we
hypothesize that phenytoin may increase erythropoietin level directly through inhibition of
calcium influx and indirectly through an increase in renin secretion and production of
angiotensin II which causes hypoxia. Considering the neuroprotective function of
erythropoietin, phenytoin may provide neuroprotection partially through stimulation of
erythropoietin production.

Correspondence: Dr. Soha Namazi, Department of Clinical Pharmacy, Faculty of
Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran. Tel: +98 711 2424128. Fax:
+982426070. E-mail: