Authors
1 Assistant Professor, Department of Anatomy & Pathology, School of Medicine, Shahed University, Tehran, Iran
2 Professor, Neurophysiology Research center, Shahed University, Tehran, Iran
3 Medical graduate, School of Medicine, Shahed University, Tehran, Iran
Abstract
Background & Aims: With regard to the neuroprotective effect of creatine in some neurological disorders like cerebral ischemia, this study was conducted to evaluate the effect of creatine in an experimental model of Parkinson’s disease (PD). Involvement of oxidative stress was also assessed. Methods: In this experimental study, male rats (n = 40) were divided into 5 groups, i.e. sham-operated (SH), high dose creatine-treated sham-operated (Cr+SH), lesioned (L), and low- and high-dose creatine-treated lesioned (Cr100+L and Cr200+L) groups. The hemi-PD early model was induced by unilateral intrastriatal injection of 6-hydroxydopamine (6-OHDA, 12.5 µg/5 µl of saline-ascorbate; left side). The Cr+SH and Cr+L groups were pretreated by creatine at doses of 100 and/or 200 mg/kg per day before surgery two times at an interval of 24 hours. Finally, the animals were tested for rotational behavior by apomorphine and the number of dopaminergic neurons in the substantia nigra pars compacta (SNC) was counted. Level of malondialdehyde (MDA), as a marker of oxidative stress, was also evaluated in midbrain homogenate. Results:, Apomorphine caused a significant contralateral turning (P < 0.001) in 6-OHDA-lesioned group and a reduction in the number of neurons on the left side of the SNC in the L group was observed in comparison with SH group (P < 0.010) 2 weeks after surgery. Creatine pretreatment caused dose-dependent decrease the rotational behavior in lesioned rats (P < 0.050 and P < 0.010), and at a dose of 200 mg/kg significantly attenuated the reduction in the number of SNC neurons (P < 0.050). Creatine treatment of lesion groups also lowered MDA level at both doses (P < 0.050). Conclusion: Oral creatine pretreatment exhibits neuroprotective effects against 6-OHDA toxicity in an experimental model of PD, as was shown by a lower rotational behavior and attenuation of neuronal loss. Its effect is partly due to the attenuation of oxidative stress.
Keywords
- Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease. Free Radic Res 2005; 39(10): 1119-25.
- Ward RJ, Lallemand F, de WP, Dexter DT. Neurochemical pathways involved in the protective effects of nicotine and ethanol in preventing the development of Parkinson's disease: potential targets for the development of new therapeutic agents. Prog Neurobiol 2008; 85(2): 135-47.
- Yuan H, Sarre S, Ebinger G, Michotte Y. Histological, behavioural and neurochemical evaluation of medial forebrain bundle and striatal 6-OHDA lesions as rat models of Parkinson's disease. J Neurosci Methods 2005; 144(1): 35-45.
- Sawada M, Sawada H, Nagatsu T. Effects of aging on neuroprotective and neurotoxic properties of microglia in neurodegenerative diseases. Neurodegener Dis 2008; 5(3-4): 254-6.
- Singh S, Ahmed R, Sagar RK, Krishana B. Neuroprotection of the nigrostriatal dopaminergic neurons by melatonin in hemiparkinsonium rat. Indian J Med Res 2006; 124(4): 419-26.
- Rose S, Ramsay CN, Jenner P. The novel adenosine A2a antagonist ST1535 potentiates the effects of a threshold dose of L-dopa in unilaterally 6-OHDA-lesioned rats. Brain Res 2007; 1133(1): 110-4.
- Hwang O. Role of oxidative Sstress in Parkinson's disease. Exp Neurobiol 2013; 22(1): 11-7.
- Hipkiss AR. Aging, Proteotoxicity, Mitochondria, Glycation, NAD and Carnosine: Possible Inter-Relationships and Resolution of the Oxygen Paradox. Front Aging Neurosci 2010; 2: 10.
- Valastro B, Dekundy A, Danysz W, Quack G. Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Behav Brain Res 2009; 197(1): 90-6.
- Andres RH, Huber AW, Schlattner U, Perez-Bouza A, Krebs SH, Seiler RW, et al. Effects of creatine treatment on the survival of dopaminergic neurons in cultured fetal ventral mesencephalic tissue. Neuroscience 2005; 133(3): 701-13.
- Yang L, Calingasan NY, Wille EJ, Cormier K, Smith K, Ferrante RJ, et al. Combination therapy with coenzyme Q10 and creatine produces additive neuroprotective effects in models of Parkinson's and Huntington's diseases. J Neurochem 2009; 109(5): 1427-39.
- Klivenyi P, Calingasan NY, Starkov A, Stavrovskaya IG, Kristal BS, Yang L, et al. Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase. Neurobiol Dis 2004; 15(3): 610-7.
- Lensman M, Korzhevskii DE, Mourovets VO, Kostkin VB, Izvarina N, Perasso L, et al. Intracerebroventricular administration of creatine protects against damage by global cerebral ischemia in rat. Brain Res 2006; 1114(1): 187-94.
- Paxinos G, Watson C. The part brain in stereotaxic coordinates. 2hd ed., San Diego, Academic press, 1986.
- Pastula DM, Moore DH, Bedlack RS. Creatine for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2010; (6): CD005225.
- Gerlach M, Riederer P. Animal models of Parkinson's disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 1996; 103(8-9): 987-1041.
- Cadet JL, Last R, Kostic V, Przedborski S, Jackson-Lewis V. Long-term behavioral and biochemical effects of 6-hydroxydopamine injections in rat caudate-putamen. Brain Res Bull 1991; 26(5): 707-13.
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