Assessment of neurotoxicity of monocrotaline, an alkaloid extracted from Crotalaria retusa in astrocyte/neuron co-culture system

Pitanga, Bruno Penas Seara; Silva, Victor Diógenes A.; Souza, Catiane; Junqueira, Huiara A.; Fragomeni, B.O.; Nascimento, Ravena Pereira do; Silva, Ana Rita; Costa, Maria de Fátima Dias; El-Bachá, Ramon dos Santos; Costa, Sílvia Lima

doi:10.1016/j.neuro.2011.07.002

Cited by 23 publications

(14 citation statements)

References 31 publications

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“…Lesions observed in our work were severe structural disorganization, edema, moderate pyknotic cells, vacuolization, and inflammatory cell infiltration. These results are according to previous studies that showed vacuolization and increase in cell body in cortical astrocyte/neuron primary co-ultures, referring to neuronal damage induced by MCT [31]. Similarly, another study showed that pyrrolizidine alkaloid monocrotaline induced cytotoxicity, morphological changes, and oxidative and genotoxic damages to glial cells, using the human glioblastoma cell line GL-15 as a model [32].…”

Section: Discussionsupporting

confidence: 88%

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

Honório

Vasconcelos

Rodrigues

et al. 2012

Oxidative Medicine and Cellular Longevity

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This work was designed to study MCT effect in histopathological analysis of hippocampus (HC) and parahippocampal cortex (PHC) and in oxidative stress (OS) parameters in brain areas such as hippocampus (HC), prefrontal cortex (PFC), and striatum (ST). Swiss mice (25–30 g) were administered a single i.p. dose of MCT (5, 50, or 100 mg/kg) or 4% Tween 80 in saline (control group). After 30 minutes, the animals were sacrificed by decapitation and the brain areas (HC, PHC, PFC, or ST) were removed for histopathological analysis or dissected and homogenized for measurement of OS parameters (lipid peroxidation, nitrite, and catalase) by spectrophotometry. Histological evaluation of brain structures of rats treated with MCT (50 and 100 mg/kg) revealed lesions in the hippocampus and parahippocampal cortex compared to control. Lipid peroxidation was evident in all brain areas after administration of MCT. Nitrite/nitrate content decreased in all doses administered in HC, PFC, and ST. Catalase activity was increased in the MCT group only in HC. In conclusion, monocrotaline caused cell lesions in the hippocampus and parahippocampal cortex regions and produced oxidative stress in the HC, PFC, and ST in mice. These findings may contribute to the neurological effects associated with this compound.

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Section: Discussionsupporting

confidence: 88%

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

Honório

Vasconcelos

Rodrigues

et al. 2012

Oxidative Medicine and Cellular Longevity

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“…Once the toxin disappears, the excess smooth endoplasmic reticulum membrane is removed by a process dependent on lysosomes, called autophagocytosis. Cytoplasmic vacuoles were evident in co-cultures of astrocytes/neurons (Pitanga et al, 2011) but not in primary cultures of astrocytes treated with MCT (Barreto et al, 2006), which confirms the hypothesis that metabolic properties of MCT are dependent on interactions between neurons and glia.…”

Section: Understanding the Mct Metabolism Of Astrocytes And Its Relatmentioning

confidence: 79%

“…By applying immunocytochemistry in co-cultures exposed to 10–100 μM MCT, we found that MCT disrupts β-tubulin III staining, which suggested that the polymerization of this protein failed in neurons. Moreover, by western blot analysis, we observed a strong decrease in the β-tubulin III expression in protein extracts, which indicated protein destabilization had occurred (Pitanga et al, 2011). These findings support the theory that the neuronal β-tubulin III cytoskeletal protein is a molecular target of MCT or its metabolites, which might interfere with the dynamics of stabilization of microtubular proteins.…”

Section: Understanding the Mct Metabolism Of Astrocytes And Its Relatmentioning

confidence: 90%

“…We also observed that treatment with 100 μM MCT depleted GSH in co-cultures of astrocytes/neurons and that the GSH depletion was reversed when the cytochrome P450 enzymatic system was inhibited by cimetidine, a potent inhibitor of hepatic cytochrome P450 (Chang et al (1992)). These findings indicate that GSH depletion is dependent on the metabolism and synthesis of active metabolites via the P450 system and that this phenomenon is involved in MCT-induced neurotoxicity (Pitanga et al, 2011). Taken together, these in vitro studies of primary rat cultures of astrocytes or neurons provide new information on the mechanisms of MCT toxicity in different cell populations in the CNS and their relationship to neurological phenomena observed in intoxicated animals.…”

Section: Understanding the Mct Metabolism Of Astrocytes And Its Relatmentioning

confidence: 98%

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

Pitanga¹,

Nascimento²,

Silva³

et al. 2012

Front. Pharmacol.

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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.

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“…19 MCT is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) derived from the seeds of the Crotalaria spectabilis plant, which may cause damages to the central nervous system attributing to the toxic effects of PA. 20 Evidence reported that MCT could injure pulmonary endothelial cells, thus resulting in a progressive damage of the endothelial cell membrane and loss of endothelial caveolin-1 with subsequent dysfunction of the endothelial cells, vascular remodeling, and PH. 19 MCT is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) derived from the seeds of the Crotalaria spectabilis plant, which may cause damages to the central nervous system attributing to the toxic effects of PA. 20 Evidence reported that MCT could injure pulmonary endothelial cells, thus resulting in a progressive damage of the endothelial cell membrane and loss of endothelial caveolin-1 with subsequent dysfunction of the endothelial cells, vascular remodeling, and PH.…”

Section: Discussionmentioning

confidence: 99%

Exploration of the Notch3‐HES5 signal pathway in monocrotaline‐induced pulmonary hypertension using rat model

Chen

et al. 2019

Congenital Heart Disease

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Objective This study explores the role of the Notch3‐HES5 signal pathway in monocrotaline‐induced pulmonary hypertension (PH) using rat models. Method Sprague Dawley rats (n = 45) were randomly grouped into normal group, control group, and model group. Rats in the model group were used to establish the PH rat model. Four weeks after model establishment, right catheterization was used to measure the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) to analyze hemodynamic changes. The severity of PH was assessed by the right ventricular hypertrophy index (RVHI) and percentage of media thickness (MT%). The expressions of Notch3 and HES5 were determined by ELISA and reverse transcription‐polymerase chain reaction. The correlation of mRNA expressions of Notch3 and HES5 with mPAP was analyzed. Results Rats in the model group had higher mPAP, RVSP, RVHI, and MT% as well as thicker pulmonary arterioles wall than those in the normal group. Immunohistochemistry showed Notch3 and HES5 were mainly expressed in the smooth muscle cell in pulmonary arterioles. In comparison with the normal group, rats in the model group had elevated expressions of Notch3 and HES5. The mean pulmonary arterial pressure was positively related with mRNA expressions of Notch3 and HES5. Conclusion Taken together, our study demonstrates that monocrotaline‐induced PH rats had high expressions of the Notch3‐HES5 signal pathway in the pulmonary arterioles. The signal of the Notch3‐HES5 signal pathway was positively related to the hemodynamics of the lung vasculature.

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Assessment of neurotoxicity of monocrotaline, an alkaloid extracted from Crotalaria retusa in astrocyte/neuron co-culture system

Cited by 23 publications

References 31 publications

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

Monocrotaline: Histological Damage and Oxidant Activity in Brain Areas of Mice

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

Exploration of the Notch3‐HES5 signal pathway in monocrotaline‐induced pulmonary hypertension using rat model

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