The Role of Astrocytes in Metabolism and Neurotoxicity of the Pyrrolizidine Alkaloid Monocrotaline, the Main Toxin of Crotalaria retusa

Bruno Penas Seara Pitanga,Victor Diógenes A Silva,Silvia L Costa,Ravena P Nascimento

doi:10.3389/fphar.2012.00144

Abstract

The metabolic interactions and signaling between neurons and glial cells are necessary for the development and maintenance of brain functions and structures and for neuroprotection, which includes protection from chemical attack. Astrocytes are essential for cerebral detoxification and present an efficient and specific cytochrome P450 enzymatic system. Whilst Crotalaria (Fabaceae, Leguminosae) plants are used in popular medicine, they are considered toxic and can cause damage to livestock and human health problems. Studies in animals have shown cases of poisoning by plants from the genus Crotalaria, which induced damage to the central nervous system. This finding has been attributed to the toxic effects of the pyrrolizidine alkaloid (PA) monocrotaline (MCT). The involvement of P450 enzymatic systems in MCT hepatic and pulmonary metabolism and toxicity has been elucidated, but little is known about the pathways implicated in the bioactivation of these systems and the direct contribution of these systems to brain toxicity. This review will present the main toxicological aspects of the Crotalaria genus that are established in the literature and recent findings describing the mechanisms involved in the neurotoxic effects of MCT, which was extracted from Crotalaria retusa, and its interaction with neurons in isolated astrocytes.

Highlights

The metabolic interactions and signaling between neurons and glial cells are necessary for the development and maintenance of brain functions and structures and for neuroprotection, which includes protection from chemical attack
In Brazil, the milk from goats fed with Crotalaria spectabilis was toxic to rats (Medeiros et al, 1999), and litters of rats fed with C. spectabilis or monocrotaline (MCT), the main pyrrolizidine alkaloid, had poisoned milk (Medeiros et al, 1998)
Studies of MCT metabolism in the liver and lungs of rats intoxicated with MCT show that after the alkaloids are metabolized by the P450 cytochrome system, they undergo dehydrogenation to produce dehydromonocrotaline (DHMC), which is considered a highly toxic compound (Lin et al, 2001; Wang et al, 2005)

Summary

Introduction

The metabolic interactions and signaling between neurons and glial cells are necessary for the development and maintenance of brain functions and structures and for neuroprotection, which includes protection from chemical attack. It is well known that to exert their toxic effect, PAs need to be metabolized by the hepatic and lung enzymatic P450 cytochrome system, which generates active metabolites, such as dehydroalkaloids and pyrrols (Mattocks, 1986; Couet et al, 1996; Kasahara et al, 1997).

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