Old mice present increased levels of succinate dehydrogenase activity and lower vulnerability to dyskinetic effects of 3-nitropropionic acid T.R. Rosenstock a , V.C. Abílio a, ⁎, R. Frussa-Filho a , B.H. Kiyomoto b , S.S. Smaili a a Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM) — Rua Três de Maio 100, CEP: 04044-020, São Paulo/SP, Brazil b Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo (UNIFESP/EPM) — Rua Pedro de Toledo 781, 7th floor, CEP: 04039-032, São Paulo/SP, Brazil abstract article info Article history: Received 22 December 2007 Received in revised form 24 July 2008 Accepted 4 August 2008 Available online 15 August 2008 Keywords: Huntington's disease 3-Nitropropionic acid Oxidative stress Aging Succinate dehydrogenase Orofacial dyskinesia Huntington's disease (HD) is a neurodegenerative disorder, with an age-related onset and a progressive development, characterized by choreiform movements. 3-Nitropropionic acid (3NP) induces the inhibition of succinate dehydrogenase (SDH), an increase in oxidative stress and anatomic changes that are related to the pathophysiology of HD. Hence, this toxin is a useful tool to study this pathology. This study compares the effects of 3NP on the development of orofacial dyskinesia (OD) and on SDH activity in young and old mice. Treatment with 3NP (5, 10, 15 or 20 mg/kg once a day, for four days) induced OD in young mice. Old mice presented an increase in the basal level of orofacial movement that was not potentiated by any dose of 3NP. Histochemical analyses showed that old mice presented an increase in the SDH activity. Finally, 3NP induced a decrease in SDH activity at both ages. We suggest that the 3NP-induced OD in young mice is related to the inhibition of SDH activity. In parallel, an enhancement in the basal activity of SDH could be related to the absence of a further increase in the OD presented by old mice treated with 3NP. © 2008 Elsevier Inc. All rights reserved. 1. Introduction HD is a progressive neurodegenerative disorder characterized by cognitive impairment, emotional disturbance and movement abnorm- alities (Barbeau et al., 1981) that starts in midlife and progressively leads to death (Vonsattel and DiFiglia, 1998). The first motor sign is changes in eye movements, which is followed by progressive orofacial dyskinesia (Brouillet et al., 1999). Despite the discovery of the genetic mutation of HD (Huntington's Disease Collaborative Research Group, 1993), the mechanisms of the pathogenesis of HD are still not understood. Oxi- dative stress and mitochondrial dysfunction (Petersén et al., 1999), have been proposed and seem to contribute to the appearance of motor alterations (Coyle and Puttfarcken, 1993; Browne et al., 1999; Turrens, 1997; Barja, 2004). Since mitochondria is responsible for the increase in oxidative stress, the production of reactive oxygen species (ROS) can affect the physical and chemical structures of the mitochondrial inner membrane itself, compromising cell respiration (Boveris and Chance, 1973) and energy supplies. Moreover, abnormalities in mitochondrial enzymatic activities, such as the deficiency of succinate dehydrogenase (SDH), an enzyme of the complex II of the mitochondrial respiratory chain (Gu et al., 1996; Panov et al., 2002), have also been related to a decrease in cellular energy and neuronal irreversible injury (Beal, 1998) that occur in caudate nuclei of HD patients. Besides all these features, aging, a multi-faceted process, is an important factor to be considered. The increase of ROS production with aging causes defects in the mitochondrial DNA (mtDNA) and damages to the mitochondrial components (Sato and Tauchi, 1982; Meccocci et al., 1994; Lopes et al., 2004). Some of the consistent changes are the decreased activity of several proteic complexes of the electron tran- sport chain (ETC) that lead to a decrease in energy production and a decline of the physiological conditions (Ozawa, 1997; Beckman and Ames, 1998; Mattson, 2000; Szibor and Holtz, 2003). As a result, these processes can accelerate cell death and the degenerative mechanisms (Harman, 1999; Cadenas and Davies, 2000). Therefore, the age-related onset and progressive course of HD may be due to a cyclic process involving the impairment of energy metabolism. 3-Nitropropionic acid (3NP), the metabolic product of 3-nitropropanol, is known to be responsible for an irreversible and progressive inhibition of SDH (Ludolph et al., 1992; Palfi et al., 1996), as well as cellular and metabolic dysfunction and motor deficits (Guyot et al., 1997) similar to HD (Brouillet et al., 1999). Because of these facts, the treatment with 3NP became a relevant experimental model for the study of this disease (Brouillet et al., 1999; Rosenstock et al., 2004). 3NP treatment induces, for example, the development of orofacial dyskinesia in rodents, one of the first motor signs of HD (Brouillet et al., 1999) appearing as vacuous chewing movement (Andreassen and Jorgensen, 1995; Brouillet et al., 1999; Rosenstock et al., 2004). This behavioral parameter seems to be related to an increase in oxidative stress (Abílio et al., 2002, 2003, 2004; Faria et al., 2005), one of the consequences of 3NP treatment (Rosenstock et al., 2004). Moreover, 3NP can also lead to alterations in mitochondrial Pharmacology, Biochemistry and Behavior 91 (2009) 327–332 ⁎ Corresponding author. Tel./fax: +55 11 5081 2984. E-mail address: vanabilio@uol.com.br (V.C. Abílio). 0091-3057/$ – see front matter © 2008 Elsevier Inc. 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