2,4-Dichlorophenoxyacetic Acid Disrupts the Cytoskeleton and Disorganizes the Golgi Apparatus of Cultured Neurons

Rosso, Silvana Beatriz; Cáceres, Alfredo; Duffard, Ana María Evangelista de; Duffard, Ricardo; Quiroga, Santiago

doi:10.1093/toxsci/56.1.133

Cited by 47 publications

(18 citation statements)

References 43 publications

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“…In particular, rotenone appears to affect MT polymerization (Brinkley et al, 1974; Marshall and Himes, 1978), and dopaminergic neurons may be particularly sensitive to this toxin (Ren et al, 2005). Similar observations have been made with additional agents employed to model certain aspects of PD, such as herbicides (Holy, 1998; Rosso et al, 2000) and MPTP (Cappelletti et al, 1999; Cappelletti et al, 2005; Cartelli et al, 2010). Notably, treating mice with MPTP leads to increased MT dynamicity, consistent with findings from culture systems (Fanara et al, 2012).…”

Section: Evidence Of Mt Abnormalities In Other Neurodegenerative Condsupporting

confidence: 63%

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Brunden

Lee

Smith

et al. 2017

Neurobiology of Disease

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Many neurodegenerative diseases are characterized by deficiencies in neuronal axonal transport, a process in which cellular cargo is shuttled with the aid of molecule motors from the cell body to axonal termini and back along microtubules (MTs). Proper axonal transport is critical to the normal functioning of neurons, and impairments in this process could contribute to the neuronal damage and death that is characteristic of neurodegenerative disease. Although the causes of axonal transport abnormalities may vary among the various neurodegenerative conditions, in many cases it appears that the transport deficiencies result from a diminution of axonal MT stability. Here we review the evidence of MT abnormalities in a number of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and traumatic brain injury, and highlight the potential benefit of MT-stabilizing agents in improving axonal transport and nerve function in these diseases. Moreover, we discuss the challenges associated with the utilization of MT-stabilizing drugs as therapeutic candidates for neurodegenerative conditions.

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Section: Evidence Of Mt Abnormalities In Other Neurodegenerative Condsupporting

confidence: 63%

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Brunden

Lee

Smith

et al. 2017

Neurobiology of Disease

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“…PD is often modeled through the treatment of neuron cultures or rodents with environmental toxins such as rotenone, as these agents induce dopaminergic neuropathology that resembles certain aspects of PD 47 . Interestingly, rotenone appears to directly affect MT polymerization 48-50 , as do several other toxins used in PD models, including MPTP 51, 52 and certain herbicides 53, 54 .…”

Section: 1 Evidence Of Mt and Axonal Transport Dysfunction In Neuromentioning

confidence: 99%

Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease

Brunden

Trojanowski

Smith

et al. 2014

Bioorganic & Medicinal Chemistry

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Microtubules (MTs)1, cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders.

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“…In addition, we have observed that 2,4-D not only impaired neurite outgrowth, disrupted the cytoskeleton, and disorganized the Golgi apparatus (Rosso et al 2000), but also affected some selective enzymatic activities and increased ROS levels in cerebellar granule cells (CGC) culture (Bongiovanni et al 2007). In agreement with the above observations, some changes in protective enzymes in human tissues have also been described by others (Bukowska et al 2000;Bukowska 2003).…”

Section: Introductionmentioning

confidence: 99%

Adverse Effects of 2,4-Dichlorophenoxyacetic Acid on Rat Cerebellar Granule Cell Cultures Were Attenuated by Amphetamine

et al. 2010

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2,4-Dichlorophenoxyacetic acid (2,4-D), a worldwide-used herbicide, has been shown to produce a wide range of adverse effects in the health--from embryotoxicity and teratogenicity to neurotoxicity--of animals and humans. In this study, neuronal morphology and biochemical events in rat cerebellar granule cell (CGC) cultures have been analyzed to define some of the possible mechanisms involved in 2,4-D-induced cell death. For that purpose, amphetamine (AMPH) that has been shown to accelerate the recovery of several functions in animals with brain injury has been used as a pharmacologycal tool and was also investigated as a possible protecting agent. Addition of 2,4-D to CGC cultures produced a drastic decrease in cell viability, in association with an increased incidence of necrosis and apoptosis, and an increased level of reactive oxygen species, a decrease in glutathione content, and an abnormal activity of some enzymes with respect to the control group. The adverse effects of 2,4-D were partly attenuated in presence of AMPH. Some deleterious effects on several ultrastructural features of the cells, as well as the enhanced incidence of apoptosis, were partially preserved in AMPH-protected cultures as compared with those which were exposed to 2,4-D alone. The collected evidences (1) confirms the previously observed, deleterious effects of 2.4D on the same or a similar model; (2) suggests that the 2,4-D-induced apoptosis could have been mediated by or associated to an oxidative imbalance in the affected cells, and (3) shows some evidence of a protective effect of AMPH on 2,4-D-induced cell death, which could have been exerted through a reduction in the oxidative stress.

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2,4-Dichlorophenoxyacetic Acid Disrupts the Cytoskeleton and Disorganizes the Golgi Apparatus of Cultured Neurons

Cited by 47 publications

References 43 publications

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease

Adverse Effects of 2,4-Dichlorophenoxyacetic Acid on Rat Cerebellar Granule Cell Cultures Were Attenuated by Amphetamine

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