Abstract
Neurons in the CA1 hippocampus, striatum, or reticular nucleus of the thalamus are most often damaged during brain ischemia. An abundant glutamatergic innervation that drives excitotoxity and the vulnerability of γ-aminobutyric acid-ergic (GABAergic) neurons to such stress has been suggested for the neuronal cell death of these areas (1–4). Intoxication with 3-nitropropionic acid (3-NPA), a mycotoxin that inhibits succinate dehydrogenase irreversibly, leads to high-energy (ATP) deficiency (5–7) and production of free radicals (8, 9), thus results in cellular hypoxia and cellular damage. Systemic intoxication with 3-NPA induces striatum-selective lesions with motor symptoms, reminiscent of Huntington’s disease (10–13). Enhancement of excitotoxicity (5–7) and breakdown of the blood-brain barrier (14–17) have been suggested but mechanisms are not yet well understood. 3-NPA-induced striatal lesions are located in the lateral part of the striatum associated with dysfunction of the blood-brain barrier (17). This suggests that specific mechanisms are operating in this area of the brain. In this chapter, we propose that the dopamine (DA) toxicity due to DA overflow and the vulnerability of the lateral striatal (1STR) artery resulting from damage to endothelial cells and end-feet of astrocytes contribute to development of striatum-selective lesions following systemic 3-NPA intoxication. These characteristics may be major predisposing factors for neurodegenerative diseases, autoimmune diseases, or stroke that often affect the striatum.
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References
Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988; 1: 623–634.
DiFiglia M. Excitotoxic injury of the neostriatum: a model for Huntington’s disease. Trends Neurosci 1990; 13: 286–289.
Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and neuro-degenerative disease. Trends Pharmacol Sci 1990; 11: 379–387.
Nishino H, Czurko A, Fukuda A, et al. Pathophysiological process after transient ischemia of the middle cerebral artery in the rat. Brain Res Bull 1994; 35: 51–56.
Beal MF. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illness? Ann Neurol 1992; 31: 119–130.
Beal MF, Brouillet E, Jenkins BG, et al. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 1993; 13: 4181–4192.
Simpson JR, Isacson O. Mitochondrial impairment reduces the threshold for in vivo NMDA-mediated neuronal death in the striatum. Exp Neurol 1993; 121: 57–64.
Beal MF, Ferrante RJ, Henshaw R, et al. 3-Nitropropionic acid neurotoxicity is attenuated in copper/zinc superoxide dismutase transgenic mice. J Neurochem 1995; 65: 919–922.
Schulz JB, Matthews RT, Jenkins BG, et al. Blockade of neuronal nitric oxide synthase protects against excitotoxicity in vivo. J Neurosci 1995; 15: 8419–8429.
Brouillet M, Hantraye P, Ferrante RT, et al. Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci USA 1995; 92: 7105–7109.
Shimano Y, Kumazaki M, Sakurai T, et al. Chronically administered 3-nitropropionic acid produces selective lesions in the striatum and reduces muscle tonus. Obesity Res 1995; 3 (Suppl 5): 779s - 784s.
Borlongan CV, Koutouzis TK, Freeman TB, et al. Behavioral pathology induced by repeated systemic injections of 3-nitropropionic acid mimics the motoric symptoms of Huntington’s disease. Brain Res 1995; 679: 254–257.
Palfi S, Ferrante RJ, Brouillet E, et al. Chronic 3-nitropropionic acid treatment in baboons replicates the cognitive and motor deficits of Huntington’s disease. J Neurosci 1996; 16: 3019–3025.
Hamilton BF, Gould DH. Nature and distribution of brain lesions in rats intoxicated with 3-nitropropionic acid: a type of hypoxic (energy deficient) brain damage. Acta Neuropathol 1987; 72: 286–297.
Hamilton F, Gould DH. Correlation of morphologic brain lesions with physiologic alterations and blood—brain barrier impairment in 3-nitropropionic acid toxicity in rats. Acta Neuropathol 1987; 74: 67–74.
Nishino H, Shimano Y, Kumazaki M, et al. Chronically administered 3-nitropropionic acid induces striatal lesions attributed to dysfunction of the blood—brain barrier. Neurosci Lett 1995; 186: 161–164.
Nishino H, Kumazaki M, Fukuda A, et al. Acute 3-nitropropionic acid intoxication induces striatal astrocytic cell death and dysfunction of the blood—brain barrier: involvement of dopamine toxicity. Neurosci Res 1997; 27: 343–355.
He F, Zhang S, Zhang C, et al. Extrapyramidal lesions induced by mildewed sugar cane poisoning. Three case reports. Chin Med J 1987; 67: 395–396.
Nishino H, Nakajima K, Kumazaki M, et al. Estrogen protects against while testosterone exacerbates vulnerability of the lateral striatal artery to chemical hypoxia by 3-nitropropionic acid. Neurosci Res 1998; 30: 303–312.
Pei G, Ebendal T. Specific lesions in the extrapyramidal system of the rat brain induced by 3-nitropropionic acid (3-NPA). Exp Neurol 1995; 132: 105–115.
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Kumazaki, M., Ungsuparkorn, C., Deshpande, S.B., Fukuda, A., Nishino, H. (2000). Mechanisms of Action of 3-Nitropropionic Acid. In: Sanberg, P.R., Nishino, H., Borlongan, C.V. (eds) Mitochondrial Inhibitors and Neurodegenerative Disorders. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-692-8_11
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DOI: https://doi.org/10.1007/978-1-59259-692-8_11
Publisher Name: Humana Press, Totowa, NJ
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