Excitotoxins, Aging, and Environmental Neurotoxins: Implications for Understanding Human Neurodegenerative Diseases

Dawson, Ralph; Beal, M. Flint; Bondy, S. C.; Monte, Donato A. Di; Isom, Gary E.

doi:10.1006/taap.1995.1163

Cited by 107 publications

(41 citation statements)

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“…McLean and Ward (27) reported that dihydroartemisinin binds to mitochondrial and endoplasmic membranes in differentiated neuronal cell cultures. It is known that inhibitors of the respiratory chain such as KCN induce delayed Parkinsonism and a basal ganglion disease that is associated with locomotor impairment (9,20,23). In vitro, this neurodegenerative effect is demonstrated by a decrease in the neurofilaments (35).…”

Section: Discussionmentioning

confidence: 99%

Neurotoxic Mode of Action of Artemisinin

Schmuck

Roehrdanz

Haynes

et al. 2002

Antimicrob Agents Chemother

116

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We recently described a screening system designed to detect neurotoxicity of artemisinin derivatives based on primary neuronal brain stem cell cultures (G. Schmuck and R. K. Haynes, Neurotoxicity Res. 2:37-49, 2000). Here, we probe possible mechanisms of this brain stem-specific neurodegeneration, in which artemisinin-sensitive neuronal brain stem cell cultures are compared with nonsensitive cultures (cortical neurons, astrocytes). Effects on the cytoskeleton of brain stem cell cultures, but not that of cortical cell cultures, were visible after 7 days. However, after a recovery period of 7 days, this effect also became visible in cortical cells and more severe in brain stem cell cultures. Neurodegeneration appears to be induced by effects on intracellular targets such as the cytoskeleton, modulation of the energy status by mitochondrial or metabolic defects, oxidative stress or excitotoxic events. Artemisinin reduces intracellular ATP levels and the potential of the inner mitochondrial membrane below the cytotoxic concentration range in all three cell cultures, with these effects being most dominant in the brain stem cultures. Surprisingly, there were substantial effects on cortical neurons after 7 days and on astrocytes after 1 day. Artemisinin additionally induces oxidative stress, as observed as an increase of reactive oxygen species and of lipid peroxidation in both neuronal cell types. Interestingly, an induction of expression of AOE was only seen in astrocytes. Here, manganese superoxide dismutase (MnSOD) expression was increased more than 3-fold and catalase expression was increased more than 1.5-fold. In brain stem neurons, MnSOD expression was dose dependently decreased. Copper-zinc superoxide dismutase and glutathione peroxidase, two other antioxidant enzymes that were investigated, did not show any changes in their mRNA expression in all three cell types after exposure to artemisinin.Chemically induced neurodegeneration is characterized by different patterns of neuronal cell death, gliosis, swollen or destroyed axons, or destruction of the myelin sheet. Effects on biochemical targets possibly precede manifestation of these morphologic endpoints. Therefore, not only cell viability but also integrity of the cytoskeleton and neuronal energy state should be considered (6). Primary neuronal cell cultures derived from the embryonal rat cortex have been used as a model for neuron-specific toxicity of various neurotoxicants, whose neurotoxic mode of action has been well characterized (36). The neurotoxicants include chemicals that primarily target the cytoskeleton, such as the organophosphate mipafox and ␤,␤-iminodipropionitrile, and substances that primarily impair the cellular energy supply, such as potassium cyanide and 3-nitropropionic acid. Also included were compounds such as acrylamide and 2,5-hexanedione, which act on both cytoskeleton and cellular energy production, and the well-known excitotoxin N-methyl-D-aspartate, which indirectly affects mitochondria.Artemisinin, isolated from the traditional C...

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Section: Discussionmentioning

confidence: 99%

Neurotoxic Mode of Action of Artemisinin

Schmuck

Roehrdanz

Haynes

et al. 2002

Antimicrob Agents Chemother

116

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“…In addition to their ability to transmit vital excitatory CNS signals, they have shown to cause neuronal dysfunction by over stimulation of neurons. The ensuing excitotoxicity may be a causative factor in multitude of neurodegenerative diseases (Dawson et al, 1995;Dong et al, 2009). Astrocytes play a crucial role in regulating and maintaining the extracellular chemical milieu of the central nervous system under physiological conditions (Eid et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Restoration Of Glutamine Synthetase Activity, Nitric Oxide Levels And Amelioration Of Oxidative Stress By Propolis In Kainic Acid Mediated Excitotoxicity

Swamy

Norlina

Azman

et al. 2014

Afr. J. Trad. Compl. Alt. Med.

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Background: Propolis has been proposed to be protective on neurodegenerative disorders. To understand the neuroprotective effects of honeybee propolis, glutamine synthetase (GS) activity, nitric oxide (NO), thiobarbituric acid reactive substances (TBARS) and total antioxidant status (TAS) were studied in different brain regions-cerebral cortex (CC), cerebellum (CB) and brain stem (BS) of rats supplemented with propolis and subjected to kainic acid (KA) mediated excitotoxicity. Materials and Methods: Male Sprague-Dawley rats were divided into four groups; Control group and KA group received vehicle and saline. Propolis group and propolis + KA group were orally administered with propolis (150mg/kg body weight), five times every 12 hours. KA group and propolis + KA group were injected subcutaneously with kainic acid (15mg/kg body weight) and were sacrificed after 2 hrs and CC, CB and BS were separated homogenized and used for estimation of GS activity, NO, TBARS, and TAS concentrations by colorimetric methods. Results were analyzed by oneway ANOVA, reported as mean + SD from 6 animals, and p<0.05 considered statistically significant. Results: NO was increased (p< 0.001) and GS activity was decreased (p< 0.001) in KA treated group compared to control group as well as propolis + KA treated group. TBARS was decreased and TAS was increased (p< 0.001) in propolis + KA treated group compared KA treated group. Conclusion:This study clearly demonstrated the restoration of GS activity, NO levels and decreased oxidative stress by propolis in kainic acid mediated excitotoxicity. Hence the propolis can be a possible potential candidate (protective agent) against excitotoxicity and neurodegenerative disorders.

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“…We have previously speculated that enhanced turnover of dopamine may itself be neurotoxic, because the metabolism and auto-oxidation of dopamine generates cellular oxidative stress (Dawson et al, 1995) and high levels of dopamine in the brain can be neurotoxic (Filloux and Townsend, 1993). However, we would expect that cell toxicity would be reflected in a loss of striatal dopamine, but this effect was not observed, perhaps due to the short duration of exposure (two weeks).…”

Section: Resultsmentioning

confidence: 99%

Insecticide Exposure in Parkinsonism

Bloomquist¹,

Klein²

2004

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Excitotoxins, Aging, and Environmental Neurotoxins: Implications for Understanding Human Neurodegenerative Diseases

Cited by 107 publications

References 0 publications

Neurotoxic Mode of Action of Artemisinin

Neurotoxic Mode of Action of Artemisinin

Restoration Of Glutamine Synthetase Activity, Nitric Oxide Levels And Amelioration Of Oxidative Stress By Propolis In Kainic Acid Mediated Excitotoxicity

Insecticide Exposure in Parkinsonism

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