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

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.

Juliprosopine and Juliprosine from Prosopis juliflora Leaves Induce Mitochondrial Damage and Cytoplasmic Vacuolation on Cocultured Glial Cells and Neurons

“…However, in another study, conducted in astrocyte primary cultures enriched with microglia, significant reductions in mitochondrial activity and a loss of membrane integrity were observed after exposure to 3 μg/mL TAE or F32 obtained from P. juliflora leaves . In the central nervous system, astrocytes are the cells that respond to insults and metabolize xenobiotics as a mechanism of neuronal protection and stand out by having enzymatic machinery that allows them to develop both the phase I metabolism enzyme isoforms by system cytochrome P450 metabolism and phase II by glutathione transferase isoforms. − It is possible that the resistance of glial cell cultures and neuron/glial cell cocultures to alkaloids is a result of the metabolism of the astrocytes, and further studies may be performed to improve our understanding its relation with neurotoxicity.…”

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases

“…, CYP3A and CYP2B, to produce highly reactive 6,7-dihydropyrrolizine (“pyrrolic”) ester metabolites [6,7-DHP-esters ( 2 )] (Figure ). Hepatocytes, , astrocytes, and neurons − are particularly relevant cells in which metabolic activation of 1,2-dehydroPAs by CYP450 enzymes occurs. The 6,7-DHP-ester ( 2 ) metabolites initially produced are powerful biological alkylating agents with a very short in vivo half-life of seconds. , The diverse aliphatic acids esterifying the hydroxyl groups on C7 and C9 of the aromatic 6,7-DHP ring system are rapidly displaced by nucleophilic groups ( e.g.…”

Ethno-medicinal Use of Crotalaria retusa L. (Fabaceae), a Pyrrolizidine Alkaloid Toxic Plant

“…Alkaloids, saponins, tannins, steroids, flavonoids [12] Anti-DPPH (IC50= 57.5 µg/mL) and bactericidal [8] Fever and skin diseases [11] Saponins, tannins, alkaloids, flavonoids, reduce sugars [10] Thrombolytic [10] Highly sought in love matters, acceptance [5] Monocrotaline [17] Leishmanicide action [18] Uterine hemorrhages, dysentery, and inflamed wounds [17] Monocrotaline and tricodesmine alkaloid [15,19] Neurotoxic [15] Eye infection Sheila [11]…”

“…However, the genotoxic, neurotoxic and acute poisoning properties of C. retusa on human and animal are well documented [13,14]. According to previous pharmacological investigations, the alkaloid monocrotaline, an abundant pyrrolizidine alkaloid from C. retusa leaves and seed is responsible of the toxicity of C. retusa [13,15]. So, alkaloid monocrotaline is a hepatotoxic alkaloid causing many liver diseases and altering behaviors, such as dullness or hyper excitability, head pressing against physical barriers, compulsive walking or circling and occasionally, violent uncontrollable galloping [13].…”