- Email: [email protected]
Selenium partially reverses the depletion of striatal dopamine and its metabolites in MPTP-treated C57BL mice
Neurochemistry International 57 (2010) 489–491
Contents lists available at ScienceDirect
Neurochemistry International journal homepage: www.elsevier.com/locate/neuint
Rapid communication
Selenium partially reverses the depletion of striatal dopamine and its metabolites in MPTP-treated C57BL mice Haseeb Ahmad Khan * Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 April 2010 Received in revised form 17 June 2010 Accepted 28 June 2010 Available online 7 July 2010
Oxidative stress and inflammation have been implicated in idiopathic Parkinson’s disease as well as in the mouse model of this disorder induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Selenium possesses both antioxidant and anti-inflammatory properties; thus we studied the effect of selenium supplementation on MPTP-induced dopaminergic neurotoxicity in mice. C57BL male mice were treated with MPTP (30 mg/kg, i.p.), daily for 4 days. Sodium selenite (Se) was administered in the doses of 0, 1, 2 and 3 mg/kg, 30 min prior to the administration of MPTP. One group of animals served as control (saline only) and another group as Se alone (3 mg/kg). The animals were sacrificed at 24 h after the last dose of MPTP. The striata were isolated and analyzed for dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Administration of MPTP significantly depleted striatal DA (6.78 0.80 mg/g) as compared to control animals (19.32 0.77 mg/g) which was significantly prevented by co-treatment with 3 mg/kg dose of Se (12.28 0.97 mg/g). MPTP caused significant reduction in striatal DOPAC but the decrease in HVA levels was not significant. Although Se dosedependently reversed MPTP-induced decreases in DOPAC and HVA levels, these effects were statistically not significant. These findings indicate a significant impairment of dopaminergic neurotransmission by MPTP which is partially reversed by Se treatment. ß 2010 Elsevier Ltd. All rights reserved.
Keywords: Parkinson disease MPTP Selenium Dopamine Antioxidant Inflammation
1. Introduction Parkinson’s disease is a movement disorder caused by the degeneration of nigrostriatal dopaminergic neurons in substantia nigra pars compacta resulting in the deficiency of neurotransmitter dopamine (DA) in the striatum. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin of dopaminergic neurons in substantia nigra and striatum of rodents and primates and produces similar behavioral and biochemical changes as observed in Parkinson’s disease (Ballard et al., 1985). MPTP-treated mice serve as the most convenient and extensively used animal model of Parkinson’s disease. The exact mechanism of MPTPinduced dopaminergic neurotoxicity is not clear. A putative role of oxygen-derived free radicals (ODFR) has been suggested in progressive neuronal degeneration by MPTP (Chiueh et al., 1994). Inhibition of ODFR by antioxidants offers beneficial effects in MPTP-induced neurodegeneration (Park et al., 2004; Li et al., 2002; Tariq et al., 2001). However, most currently available
* Current address: Department of Botany and Microbiology, College of Science, King Saud University, Bld 5, P.O. Box 2455, Riyadh 11451, Saudi Arabia. Tel.: +966 1 4674712. E-mail address: [email protected]. 0197-0186/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2010.06.020
antioxidants cannot readily penetrate the blood–brain barrier (BBB) after systemic administration, warranting trials for novel BBB compatible antioxidant therapies (Bahat-Stroomza et al., 2005). Recently, an important role of inflammation has been implicated in the pathogenesis of Parkinson’s disease (Pfeiffer, 2009; Long-Smith et al., 2009). Involvement of inflammatory mediators has also been reported in MPTP-induced neurodegeneration (Kurkowska-Jastrzebska et al., 1999; Khan, 2004). Mandel et al. (2002) observed an important link between MPTP-induced dopaminergic toxicity and an early stage deregulation of genes involved in inflammatory process. MPTP produces significant activation of phagocytic response well before the onset of dopaminergic toxicity suggesting the involvement of potentially noxious mediators that trigger the pathways for neurodegeneration (Khan, 2004). Drugs with the ability to counteract inflammation and reduce microglial activation have been shown to attenuate MPTP-induced neurotoxicity (Kurkowska-Jastrzebska et al., 2004). Selenium is an essential trace element with potent antioxidant (Battin et al., 2006) and anti-inflammatory properties (Roberts, 1963). The metabolism of selenium by the brain differs from other organs; the preferential retention of selenium in the brain at times of its deficiency suggests its important functions in central nervous
490
[(Fig._1)TD$IG]
H.A. Khan / Neurochemistry International 57 (2010) 489–491
system (Benton, 2002). Earlier studies have documented the effects of dietary supplementation/deficiency of selenium on dopaminergic toxicity of MPTP in mice (Kim et al., 2000; Vizuete et al., 1994; Sutphin and Buckman, 1991). This study reports the effect of systemic administration of selenium (more accurate dosing as compared to dietary supplementation) on striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in MPTP-treated mice. 2. Materials and methods 2.1. Animals and doses C57BL male mice (35–40 g bodyweight) were housed in a temperature controlled room and maintained on a 12 h light–dark cycles. The animals were divided into 6 groups of 6 animals each and provided with free access to standard laboratory food and tap water. After 3 days acclimatization period, 4 groups of mice were treated with MPTP (30 mg/kg, i.p.) daily for 4 days; 3 of these groups also received i.p. injections of sodium selenite (Se) in the doses of 1, 2 and 3 mg/kg respectively, 30 min before MPTP. One of the groups served as control and received normal saline whereas another group served as Se alone group and treated with 3 mg/kg of Se (without MPTP), daily for 4 days. The animals were sacrificed at 24 after the last dosing. The striata were isolated from the cerebrum and immediately frozen in liquid nitrogen and then stored at 80 8C until analyzed. 2.2. Analysis of striatal DA and its metabolites The analysis of DA and its metabolites, DOPAC and HVA, in the striatum was carried out according to the procedure described earlier (Tariq et al., 2001). The striata were homogenized in 0.1 M perchloric acid containing 0.05% EDTA and centrifuged. The supernatant was filtered using 0.45 mm pore filter and analyzed by HPLC. A mixture of 0.1 M citric acid monohydrate, 0.1 M sodium acetate, 7% methanol, 100 mM EDTA and 0.01% sodium octane sulfonic acid was used as mobile phase, and the analytes were detected by an electrochemical detector following 20 ml injection of the sample in the mBondapak C18 reversed phase analytical column. 2.3. Statistics The effects of different doses of selenium on MPTP induced changes in striatal DA and its metabolites were evaluated by the one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test. P values less than 0.05 were considered as statistically significant.
3. Results Administration of MPTP significantly depleted striatal DA levels as compared to control animals (6.78 0.80 mg/g versus 19.32 0.77 mg/g, ANOVA F = 41.86, P = 0.000) whereas Se alone did not affect striatal DA levels (18.71 1.16 mg/g). Co-treatment of mice with Se dose-dependently prevented MPTP-induced depletion of striatal DA however this effect was statistically significant only with the high dose (3 mg/kg) of Se (12.28 0.97 mg/g) (Fig. 1a). There was a significant reduction in striatal DOPAC following MPTP treatment (ANOVA F = 6.354, P = 0.000) (Fig. 1b) whereas the MPTP-induced decrease in HVA was not statistically significant (ANOVA F = 0.794, P = 0.562) (Fig. 1c). Although Se dose-dependently reversed MPTP-induced decreases in DOPAC and HVA levels, these effects were statistically not significant (Fig. 1).
4. Discussion The findings of this study indicate a significant impairment in dopaminergic neurotransmission by MPTP while Se exerts partial protection against MPTP-induced depletion of DA. An important role of selenium in dopaminergic stimulation is evidenced by increased neural activity of dopaminergic pathways in DA-rich striatum following selenium intake (Tsunoda et al., 2000). Moreover selenium has been shown to maintain the integrity of BBB thereby protecting the brain against the exposure of toxicants and other unwanted macromolecules (Oztas et al., 2001).
Fig. 1. Effect of sodium selenite (Se) on MPTP-induced depletion of striatal DA (a), DOPAC (b) and HVA (c) levels in mice brain. *P < 0.05 and **P < 0.001 versus control or sodium selenite alone (Se 3 mg/kg) group and #P < 0.05 versus MPTP alone group using Dunnett’s multiple comparison test.
Earlier studies have shown that administration of selenium significantly protects the experimental animals against methamphetamine (Imam et al., 1999) and quinolinic acid induced dopaminergic neurotoxicity (Santamaria et al., 2003). On the other hand, the deficiency of selenium significantly increased the neurotoxicities of methamphetamine (Kim et al., 2000) and MPTP
H.A. Khan / Neurochemistry International 57 (2010) 489–491
in rodents (Vizuete et al., 1994; Sutphin and Buckman, 1991). However, MPTP-induced depletions of DA, DOPAC and HVA were found to be significantly higher in selenium-deficient rats than in vitamin E-deficient rats suggesting that the glutathione-glutathione peroxidase system has a greater protector effect than vitamin E (Vizuete et al., 1994). Johannsen et al. (1991) have observed significantly lower activities of erythrocyte glutathione peroxidase (GPx) in patients with advanced PD compared to early stage of disease. A significant correlation has also been observed between GPx and the duration of PD but not the age of patients (Johannsen et al., 1991). We have noticed that an early stage proinflammatory response following MPTP treatment triggers a chain of potentially toxic pathways leading to progressive neuronal damage (Khan, 2004). Pharmacotherapies targeting the inhibition of free radicals (Park et al., 2004; Li et al., 2002; Tariq et al., 2001) and down-regulation of proinflammatory cascade (Kurkowska-Jastrzebska et al., 2004) appeared to be useful in preventing neurodegenerative sequel. Selenium possesses both antioxidant and anti-inflammatory properties and has been shown to protect experimental animals against chemically induced neurotoxicity (Imam et al., 1999; Santamaria et al., 2003). It is important to note that selenium has a very narrow dose–response boundary of therapeutic versus lethal effects; hence it must be used with extreme caution. Thus, an adjuvant regimen based on moderate doses of selenium with vitamin E could be more advantageous and safe, as has been demonstrated in animal (Beyrouty and Chan, 2006) and clinical studies (Cadet, 1986). However, more intensive basic research is needed before coming to the stage of clinical trials. Acknowledgments This study was supported by the Research Center, Armed Forces Hospital, Riyadh, Saudi Arabia. The technical assistance by Raja Abbas Manthari is gratefully acknowledged. References Bahat-Stroomza, M., Gilgun-Sherki, Y., Offen, D., et al., 2005. A novel thiol antioxidant that crosses the blood–brain barrier protects dopaminergic neurons in experimental models of Parkinson’s disease. Eur. J. Neurosci. 21, 637–646. Ballard, P.A., Tetrud, J.W., Langston, J.W., 1985. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 35, 949–956. Battin, E.E., Perron, N.R., Brumaghim, J.L., 2006. The central role of metal coordination in selenium antioxidant activity. Inorg. Chem. 45, 499–501. Benton, D., 2002. Selenium intake, mood and other aspects of psychological functioning. Nutr. Neurosci. 5, 363–374.
491
Beyrouty, P., Chan, H.M., 2006. Co-consumption of selenium and vitamin E altered the reproductive and developmental toxicity of methylmercury in rats. Neurotoxicol. Teratol. 28, 49–58. Cadet, J.L., 1986. The potential use of vitamin E and selenium in parkinsonism. Med. Hypotheses. 20, 87–94. Chiueh, C.C., Wu, R.M., Mohankumar, K.P., et al., 1994. In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. Ann. N.Y. Acad. Sci. 738, 25–36. Imam, S.Z., Newport, G.D., Islam, F., Slikker, W., Ali, S.F., 1999. Selenium, an antioxidant, protects against methamphetamine-induced dopaminergic neurotoxicity. Brain Res. 818, 575–578. Johannsen, P., Velander, G., Mai, J., Thorling, E.B., Dupont, E., 1991. Glutathione peroxidase in early and advanced Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 54, 679–682. Khan, H.A., 2004. Time course evaluation of whole blood phagocytosis in mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Inflammopharmacology 12, 81–88. Kim, H., Jhoo, W., Shin, E., Bing, G., 2000. Selenium deficiency potentiates methamphetamine-induced nigral neuronal loss; comparison with MPTP model. Brain Res. 862, 247–252. Kurkowska-Jastrzebska, I., Litwin, T., Noniec, I., et al., 2004. Dexamethasone protects against dopaminergic neurons damage in a mouse model of Parkinson’s disease. Int. Immunopharmacol. 4, 1307–1318. Kurkowska-Jastrzebska, I., Wronska, A., Kohutnicka, M., et al., 1999. The inflammatory reaction following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication in mouse. Exp. Neurol. 59, 1–8. Li, X.J., Gu, J., Lu, S.D., Sun, F.Y., 2002. Melatonin attenuates MPTP-induced dopaminergic neuronal injury associated with scavenging hydroxyl radical. J. Pineal Res. 32, 47–52. Long-Smith, C.M., Sullivan, A.M., Nolan, Y.M., 2009. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog. Neurobiol. 89, 277–287. Mandel, S., Grunblatt, E., Maor, G., Youdim, M.B., 2002. Early and late gene changes in MPTP mice model of Parkinson’s disease employing cDNA microarray. Neurochem. Res. 27, 1231–1243. Oztas, B., Kilic, S., Dural, E., Ispir, T., 2001. Influence of antioxidants on the blood– brain barrier permeability during epileptic seizures. J. Neurosci. Res. 66, 674–678. Park, S.W., Kim, S.H., Park, K.H., et al., 2004. Preventive effects of antioxidants in MPTP-induced mouse model of Parkinson’s disease. Neurosci. Lett. 363, 243–246. Pfeiffer, R.F., 2009. Neuroinflammation and Parkinson disease: the silent battleground. Neurology 73, 1434–1435. Roberts, M.E., 1963. Antiinflammation studies II. Antiinflammatory properties of selenium. Toxicol. Appl. Pharmacol. 5, 500–506. Santamaria, A., Salvatierra Sanchez, R., Vazquez Roman, B., et al., 2003. Protective effects of the antioxidant selenium on quinolinic acid induced neurotoxicity in rats: in vitro and in vivo studies. J. Neurochem. 86, 479–488. Sutphin, M.S., Buckman, T.D., 1991. Effects of low selenium diets on antioxidant status and MPTP toxicity in mice. Neurochem. Res. 16, 1257–1263. Tariq, M., Khan, H.A., Al Moutaery, K., Al Deeb, S., 2001. Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of parkinsonism in rodents. Brain Res. Bull. 54, 77–82. Tsunoda, M., Johnson, V.J., Sharma, R.P., 2000. Increase in dopamine metabolites in murine striatum after oral exposure to inorganic but not organic form of selenium. Arch. Environ. Contam. Toxicol. 39, 32–37. Vizuete, M.L., Steffen, V., Machado, A., Cano, J., 1994. 1-Methyl-4-phenylpyridinium has greater neurotoxic effect after selenium deficiency than after vitamin E deficiency in rat striatum. Eur. J. Pharmacol. 270, 183–187.
Contents lists available at ScienceDirect
Neurochemistry International journal homepage: www.elsevier.com/locate/neuint
Rapid communication
Selenium partially reverses the depletion of striatal dopamine and its metabolites in MPTP-treated C57BL mice Haseeb Ahmad Khan * Department of Biochemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
A R T I C L E I N F O
A B S T R A C T
Article history: Received 16 April 2010 Received in revised form 17 June 2010 Accepted 28 June 2010 Available online 7 July 2010
Oxidative stress and inflammation have been implicated in idiopathic Parkinson’s disease as well as in the mouse model of this disorder induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Selenium possesses both antioxidant and anti-inflammatory properties; thus we studied the effect of selenium supplementation on MPTP-induced dopaminergic neurotoxicity in mice. C57BL male mice were treated with MPTP (30 mg/kg, i.p.), daily for 4 days. Sodium selenite (Se) was administered in the doses of 0, 1, 2 and 3 mg/kg, 30 min prior to the administration of MPTP. One group of animals served as control (saline only) and another group as Se alone (3 mg/kg). The animals were sacrificed at 24 h after the last dose of MPTP. The striata were isolated and analyzed for dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Administration of MPTP significantly depleted striatal DA (6.78 0.80 mg/g) as compared to control animals (19.32 0.77 mg/g) which was significantly prevented by co-treatment with 3 mg/kg dose of Se (12.28 0.97 mg/g). MPTP caused significant reduction in striatal DOPAC but the decrease in HVA levels was not significant. Although Se dosedependently reversed MPTP-induced decreases in DOPAC and HVA levels, these effects were statistically not significant. These findings indicate a significant impairment of dopaminergic neurotransmission by MPTP which is partially reversed by Se treatment. ß 2010 Elsevier Ltd. All rights reserved.
Keywords: Parkinson disease MPTP Selenium Dopamine Antioxidant Inflammation
1. Introduction Parkinson’s disease is a movement disorder caused by the degeneration of nigrostriatal dopaminergic neurons in substantia nigra pars compacta resulting in the deficiency of neurotransmitter dopamine (DA) in the striatum. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective neurotoxin of dopaminergic neurons in substantia nigra and striatum of rodents and primates and produces similar behavioral and biochemical changes as observed in Parkinson’s disease (Ballard et al., 1985). MPTP-treated mice serve as the most convenient and extensively used animal model of Parkinson’s disease. The exact mechanism of MPTPinduced dopaminergic neurotoxicity is not clear. A putative role of oxygen-derived free radicals (ODFR) has been suggested in progressive neuronal degeneration by MPTP (Chiueh et al., 1994). Inhibition of ODFR by antioxidants offers beneficial effects in MPTP-induced neurodegeneration (Park et al., 2004; Li et al., 2002; Tariq et al., 2001). However, most currently available
* Current address: Department of Botany and Microbiology, College of Science, King Saud University, Bld 5, P.O. Box 2455, Riyadh 11451, Saudi Arabia. Tel.: +966 1 4674712. E-mail address: [email protected]. 0197-0186/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2010.06.020
antioxidants cannot readily penetrate the blood–brain barrier (BBB) after systemic administration, warranting trials for novel BBB compatible antioxidant therapies (Bahat-Stroomza et al., 2005). Recently, an important role of inflammation has been implicated in the pathogenesis of Parkinson’s disease (Pfeiffer, 2009; Long-Smith et al., 2009). Involvement of inflammatory mediators has also been reported in MPTP-induced neurodegeneration (Kurkowska-Jastrzebska et al., 1999; Khan, 2004). Mandel et al. (2002) observed an important link between MPTP-induced dopaminergic toxicity and an early stage deregulation of genes involved in inflammatory process. MPTP produces significant activation of phagocytic response well before the onset of dopaminergic toxicity suggesting the involvement of potentially noxious mediators that trigger the pathways for neurodegeneration (Khan, 2004). Drugs with the ability to counteract inflammation and reduce microglial activation have been shown to attenuate MPTP-induced neurotoxicity (Kurkowska-Jastrzebska et al., 2004). Selenium is an essential trace element with potent antioxidant (Battin et al., 2006) and anti-inflammatory properties (Roberts, 1963). The metabolism of selenium by the brain differs from other organs; the preferential retention of selenium in the brain at times of its deficiency suggests its important functions in central nervous
490
[(Fig._1)TD$IG]
H.A. Khan / Neurochemistry International 57 (2010) 489–491
system (Benton, 2002). Earlier studies have documented the effects of dietary supplementation/deficiency of selenium on dopaminergic toxicity of MPTP in mice (Kim et al., 2000; Vizuete et al., 1994; Sutphin and Buckman, 1991). This study reports the effect of systemic administration of selenium (more accurate dosing as compared to dietary supplementation) on striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in MPTP-treated mice. 2. Materials and methods 2.1. Animals and doses C57BL male mice (35–40 g bodyweight) were housed in a temperature controlled room and maintained on a 12 h light–dark cycles. The animals were divided into 6 groups of 6 animals each and provided with free access to standard laboratory food and tap water. After 3 days acclimatization period, 4 groups of mice were treated with MPTP (30 mg/kg, i.p.) daily for 4 days; 3 of these groups also received i.p. injections of sodium selenite (Se) in the doses of 1, 2 and 3 mg/kg respectively, 30 min before MPTP. One of the groups served as control and received normal saline whereas another group served as Se alone group and treated with 3 mg/kg of Se (without MPTP), daily for 4 days. The animals were sacrificed at 24 after the last dosing. The striata were isolated from the cerebrum and immediately frozen in liquid nitrogen and then stored at 80 8C until analyzed. 2.2. Analysis of striatal DA and its metabolites The analysis of DA and its metabolites, DOPAC and HVA, in the striatum was carried out according to the procedure described earlier (Tariq et al., 2001). The striata were homogenized in 0.1 M perchloric acid containing 0.05% EDTA and centrifuged. The supernatant was filtered using 0.45 mm pore filter and analyzed by HPLC. A mixture of 0.1 M citric acid monohydrate, 0.1 M sodium acetate, 7% methanol, 100 mM EDTA and 0.01% sodium octane sulfonic acid was used as mobile phase, and the analytes were detected by an electrochemical detector following 20 ml injection of the sample in the mBondapak C18 reversed phase analytical column. 2.3. Statistics The effects of different doses of selenium on MPTP induced changes in striatal DA and its metabolites were evaluated by the one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison test. P values less than 0.05 were considered as statistically significant.
3. Results Administration of MPTP significantly depleted striatal DA levels as compared to control animals (6.78 0.80 mg/g versus 19.32 0.77 mg/g, ANOVA F = 41.86, P = 0.000) whereas Se alone did not affect striatal DA levels (18.71 1.16 mg/g). Co-treatment of mice with Se dose-dependently prevented MPTP-induced depletion of striatal DA however this effect was statistically significant only with the high dose (3 mg/kg) of Se (12.28 0.97 mg/g) (Fig. 1a). There was a significant reduction in striatal DOPAC following MPTP treatment (ANOVA F = 6.354, P = 0.000) (Fig. 1b) whereas the MPTP-induced decrease in HVA was not statistically significant (ANOVA F = 0.794, P = 0.562) (Fig. 1c). Although Se dose-dependently reversed MPTP-induced decreases in DOPAC and HVA levels, these effects were statistically not significant (Fig. 1).
4. Discussion The findings of this study indicate a significant impairment in dopaminergic neurotransmission by MPTP while Se exerts partial protection against MPTP-induced depletion of DA. An important role of selenium in dopaminergic stimulation is evidenced by increased neural activity of dopaminergic pathways in DA-rich striatum following selenium intake (Tsunoda et al., 2000). Moreover selenium has been shown to maintain the integrity of BBB thereby protecting the brain against the exposure of toxicants and other unwanted macromolecules (Oztas et al., 2001).
Fig. 1. Effect of sodium selenite (Se) on MPTP-induced depletion of striatal DA (a), DOPAC (b) and HVA (c) levels in mice brain. *P < 0.05 and **P < 0.001 versus control or sodium selenite alone (Se 3 mg/kg) group and #P < 0.05 versus MPTP alone group using Dunnett’s multiple comparison test.
Earlier studies have shown that administration of selenium significantly protects the experimental animals against methamphetamine (Imam et al., 1999) and quinolinic acid induced dopaminergic neurotoxicity (Santamaria et al., 2003). On the other hand, the deficiency of selenium significantly increased the neurotoxicities of methamphetamine (Kim et al., 2000) and MPTP
H.A. Khan / Neurochemistry International 57 (2010) 489–491
in rodents (Vizuete et al., 1994; Sutphin and Buckman, 1991). However, MPTP-induced depletions of DA, DOPAC and HVA were found to be significantly higher in selenium-deficient rats than in vitamin E-deficient rats suggesting that the glutathione-glutathione peroxidase system has a greater protector effect than vitamin E (Vizuete et al., 1994). Johannsen et al. (1991) have observed significantly lower activities of erythrocyte glutathione peroxidase (GPx) in patients with advanced PD compared to early stage of disease. A significant correlation has also been observed between GPx and the duration of PD but not the age of patients (Johannsen et al., 1991). We have noticed that an early stage proinflammatory response following MPTP treatment triggers a chain of potentially toxic pathways leading to progressive neuronal damage (Khan, 2004). Pharmacotherapies targeting the inhibition of free radicals (Park et al., 2004; Li et al., 2002; Tariq et al., 2001) and down-regulation of proinflammatory cascade (Kurkowska-Jastrzebska et al., 2004) appeared to be useful in preventing neurodegenerative sequel. Selenium possesses both antioxidant and anti-inflammatory properties and has been shown to protect experimental animals against chemically induced neurotoxicity (Imam et al., 1999; Santamaria et al., 2003). It is important to note that selenium has a very narrow dose–response boundary of therapeutic versus lethal effects; hence it must be used with extreme caution. Thus, an adjuvant regimen based on moderate doses of selenium with vitamin E could be more advantageous and safe, as has been demonstrated in animal (Beyrouty and Chan, 2006) and clinical studies (Cadet, 1986). However, more intensive basic research is needed before coming to the stage of clinical trials. Acknowledgments This study was supported by the Research Center, Armed Forces Hospital, Riyadh, Saudi Arabia. The technical assistance by Raja Abbas Manthari is gratefully acknowledged. References Bahat-Stroomza, M., Gilgun-Sherki, Y., Offen, D., et al., 2005. A novel thiol antioxidant that crosses the blood–brain barrier protects dopaminergic neurons in experimental models of Parkinson’s disease. Eur. J. Neurosci. 21, 637–646. Ballard, P.A., Tetrud, J.W., Langston, J.W., 1985. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 35, 949–956. Battin, E.E., Perron, N.R., Brumaghim, J.L., 2006. The central role of metal coordination in selenium antioxidant activity. Inorg. Chem. 45, 499–501. Benton, D., 2002. Selenium intake, mood and other aspects of psychological functioning. Nutr. Neurosci. 5, 363–374.
491
Beyrouty, P., Chan, H.M., 2006. Co-consumption of selenium and vitamin E altered the reproductive and developmental toxicity of methylmercury in rats. Neurotoxicol. Teratol. 28, 49–58. Cadet, J.L., 1986. The potential use of vitamin E and selenium in parkinsonism. Med. Hypotheses. 20, 87–94. Chiueh, C.C., Wu, R.M., Mohankumar, K.P., et al., 1994. In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. Ann. N.Y. Acad. Sci. 738, 25–36. Imam, S.Z., Newport, G.D., Islam, F., Slikker, W., Ali, S.F., 1999. Selenium, an antioxidant, protects against methamphetamine-induced dopaminergic neurotoxicity. Brain Res. 818, 575–578. Johannsen, P., Velander, G., Mai, J., Thorling, E.B., Dupont, E., 1991. Glutathione peroxidase in early and advanced Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 54, 679–682. Khan, H.A., 2004. Time course evaluation of whole blood phagocytosis in mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Inflammopharmacology 12, 81–88. Kim, H., Jhoo, W., Shin, E., Bing, G., 2000. Selenium deficiency potentiates methamphetamine-induced nigral neuronal loss; comparison with MPTP model. Brain Res. 862, 247–252. Kurkowska-Jastrzebska, I., Litwin, T., Noniec, I., et al., 2004. Dexamethasone protects against dopaminergic neurons damage in a mouse model of Parkinson’s disease. Int. Immunopharmacol. 4, 1307–1318. Kurkowska-Jastrzebska, I., Wronska, A., Kohutnicka, M., et al., 1999. The inflammatory reaction following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxication in mouse. Exp. Neurol. 59, 1–8. Li, X.J., Gu, J., Lu, S.D., Sun, F.Y., 2002. Melatonin attenuates MPTP-induced dopaminergic neuronal injury associated with scavenging hydroxyl radical. J. Pineal Res. 32, 47–52. Long-Smith, C.M., Sullivan, A.M., Nolan, Y.M., 2009. The influence of microglia on the pathogenesis of Parkinson’s disease. Prog. Neurobiol. 89, 277–287. Mandel, S., Grunblatt, E., Maor, G., Youdim, M.B., 2002. Early and late gene changes in MPTP mice model of Parkinson’s disease employing cDNA microarray. Neurochem. Res. 27, 1231–1243. Oztas, B., Kilic, S., Dural, E., Ispir, T., 2001. Influence of antioxidants on the blood– brain barrier permeability during epileptic seizures. J. Neurosci. Res. 66, 674–678. Park, S.W., Kim, S.H., Park, K.H., et al., 2004. Preventive effects of antioxidants in MPTP-induced mouse model of Parkinson’s disease. Neurosci. Lett. 363, 243–246. Pfeiffer, R.F., 2009. Neuroinflammation and Parkinson disease: the silent battleground. Neurology 73, 1434–1435. Roberts, M.E., 1963. Antiinflammation studies II. Antiinflammatory properties of selenium. Toxicol. Appl. Pharmacol. 5, 500–506. Santamaria, A., Salvatierra Sanchez, R., Vazquez Roman, B., et al., 2003. Protective effects of the antioxidant selenium on quinolinic acid induced neurotoxicity in rats: in vitro and in vivo studies. J. Neurochem. 86, 479–488. Sutphin, M.S., Buckman, T.D., 1991. Effects of low selenium diets on antioxidant status and MPTP toxicity in mice. Neurochem. Res. 16, 1257–1263. Tariq, M., Khan, H.A., Al Moutaery, K., Al Deeb, S., 2001. Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of parkinsonism in rodents. Brain Res. Bull. 54, 77–82. Tsunoda, M., Johnson, V.J., Sharma, R.P., 2000. Increase in dopamine metabolites in murine striatum after oral exposure to inorganic but not organic form of selenium. Arch. Environ. Contam. Toxicol. 39, 32–37. Vizuete, M.L., Steffen, V., Machado, A., Cano, J., 1994. 1-Methyl-4-phenylpyridinium has greater neurotoxic effect after selenium deficiency than after vitamin E deficiency in rat striatum. Eur. J. Pharmacol. 270, 183–187.