Neuroprotective Effects of Caffeine on a Maternally Separated Parkinsonian Rat Model

DOI: 10.4236/jbbs.2014.42011   PDF   HTML     2,772 Downloads   4,279 Views   Citations


Early-life stress has been shown to disrupt the programming of the hypothalamic-pituitary-adrenal (HPA) axis which may have severe consequences in the development of neurological disorders later on in life. Prolonged early-life stressful events produce an exaggerated stress hormone response in the adult offspring. Chronic stress and elevated corticosterone levels have been found to exaggerate functional deficits and accelerate loss of dopamine producing neurons in a rat model of Parkinson’s disease. We investigated the neuroprotective effects of caffeine on 6-OHDA lesioned rats that were exposed to maternal separation stress. We examined behaviour of animals before and after the infusion of 6-OHDA using the step and cylinder tests. We also measured dopamine concentration in the striatum, mitochondrial membrane potential in the striatum and the total antioxidant capacity in blood plasma. Maternally separated rats displayed an impaired ability to initiate movement in the step test and a decreased percentage impaired limb use in the cylinder test. In the rats that received caffeine these motor deficits were ameliorated. Maternal separation exaggerated the lesion caused by 6-OHDA injection. However, the neuroprotective effects of caffeine were evident in both the stressed and non-stressed rats as shown by the higher dopamine concentration and total antioxidant capacity on caffeine treated rats. Maternally separated rats had higher mitochondrial membrane permeability when compared to the caffeine treated rats. We therefore conclude that caffeine ameliorated the neurodegeneration associated with 6-OHDA injection in maternally separated animals.

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T. Mpofana, W. Daniels and M. Mabandla, "Neuroprotective Effects of Caffeine on a Maternally Separated Parkinsonian Rat Model," Journal of Behavioral and Brain Science, Vol. 4 No. 2, 2014, pp. 84-91. doi: 10.4236/jbbs.2014.42011.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Y. Pan, Y. Liu, K. A. Young, Z. Zhang and Z. Wang, “Post-Weaning Social Isolation Alters Anxiety-Related Behavior and Neurochemical Gene Expression in the Brain of Male Prairie Voles,” Neuroscience Letters, Vol. 454, No. 1, 2009, pp. 67-71.
[2] C. E. Grace, S. Kim and J. M. Rogers, “Maternal Influences on Epigenetic Programming of the Developing Hypothalamic-Pituitary-Adrenal Axis,” Birth Defects Research (Part A), Vol. 91, No. 8, 2011, pp. 797-805.
[3] M. Nishi, N. Horii-Hayashi, T. Sasagawa and W. Matsunaga, “Effects of Early Life Stress on Brain Activity: Implications from Maternal Separation Model in Rodents,” General and Comparative Endocrinology, Vol. 181, 2013, pp. 306-309.
[4] L. K. Smith, N. M. Jadavji, K. L. Colwell, S. K. Perehudoff and G. A. Metz, “Stress Accelerates Neural Degeneration and Exaggerates Motor Symptoms in a Rat Model of Parkinson’s Disease,” European Journal of Neuroscience, Vol. 27, No. 8, 2008, pp. 2133-2146.
[5] G. Biagini, E. M. Pich, C. Carani, P. Marrama and L. F. Agnati, “Postnatal Maternal Separation during the Stress Hyporesponsive Period Enhances the Adrenocortical Response to Novelty in Adult Rats by Affecting Feedback Regulation in the CA1 Hippocampal Field,” International Journal of Developmental Neuroscience, Vol. 16, No. 3-4, 1998, pp. 187-197.
[6] A. Wood-Kaczmar, S. Gandhi and N. W. Wood, “Understanding the Molecular Causes of Parkinson’s Disease,” TRENDS in Molecular Medicine, Vol. 12, No. 11, 2006, pp. 521-528.
[7] F. Blandini, G. Nappi, C. Tassorelli and E. Martignoni, “Functional Changes of the Basal Ganglia Circuitry in Parkinson’s Disease,” Progress in Neurobiology, Vol. 62, No. 1, 2000, pp. 63-88.
[8] B. Goren, Z. Mimbay, N. Bilici, M. Zarifoglu, E. Ogul and E. Korfal, “Investigation of Neuroprotective Effects of Cyclooxygenase Inhibitors in the 6-Hydroxydopamine Induced Rat Parkinson Model,” Brain Research, Vol. 19, No. 3, 2009, pp. 230-236.
[9] A. M. Hemmerle, J. P. Herman and K. B. Seroogy, “Stress, Depression and Parkinson’s Disease,” Experimental Neurology, Vol. 233, No. 1, 2012, pp. 79-86.
[10] W. G. Ondo, “Motor Complications in Parkinson’s Disease,” International Journal of Neuroscience, Vol. 121, No. 2, 2011, pp. 37-44.
[11] T. M. Armentero, A. Pinna, S. Ferré, J. L. Lanciego, C. E. Müller and R. Franco, “Past, Present and Future of A2A Adenosine Receptor Antagonists in the Therapy of Parkinson’s Disease,” Pharmacology & Therapeutics, Vol. 132, No. 3, 2011, pp. 280-299.
[12] W. Poewe, “Non-Motor Symptoms in Parkinson’s Disease,” European Journal of Neurology, Vol. 15, 2008, pp. 14-20.
[13] Y. Smith, T. T. Wichman, S. A. Factor and M. R. DeLong, “Parkinson’s Disease Therapeutics: New De-velopments and Challenges since the Introduction of Levodopa,” Neuropsychopharmacology REVIEWS, Vol. 37, No. 1, 2012, pp. 213-246.
[14] K. Xu, Y. Xu, D. Brown-Jermyn, J. Chen, A. Ascherio, D. E. Dluzen and M. A. Schwarzschild, “Estrogen Prevents Neuroprotection by Caffeine in the Mouse 1-Methyl-4- Phenyl-1,2,3,6-Tetrahydropyridine Model of Parkinson’s Disease,” The Journal of Neuroscience, Vol. 26, No. 2, 2006, pp. 535-541.
[15] S. E. Seidl and J. A. Potashkin, “The Promise of Neuroprotective Agents in Parkinson’s Disease,” Neuroprotection in Parkinson’s Disease, Vol. 2, No. 68, 2011, pp. 1-19.
[16] A. Ho, “Two Wrongs Make A Right: Nicotine and Caffeine as Defensive Agents against Parkinson’s Disease,” Nutrition Bytes, Vol. 8, No. 2, 2002, pp. 1-8.
[17] R. E. Moo-Puc, J. L. Góngora-Alfaro, F. J. Alvarez-Cervera, J. C. Pineda, G. Arankowsky-Sandoval and H. López, “Caffeine and Muscarinic Antagonists Act in Synergy to Inhibit Haloperidol-Induced Catalepsy,” Neuropharmacology, Vol. 45, No. 4, 2003, pp. 493-503.
[18] J. L. Tillerson, A. D. Cohen, J. Philhower, G. W. Miller, M. J. Zigmond and T. Schallert, “Forced Limb-Use Effects on the Behavioural and Neurochemical Effects of 6-Hydroxydopamine,” The Journal of Neuroscience, Vol. 21, No. 12, 2001, pp. 4427-4435.
[19] U. Ungerstedt, “Postsynaptic Supersensitivity after 6-Hydroxy-Dopamine Induced Degeneration of the Nigro-Striatal Dopamine System,” Acta Physiological Scandinavica Supplementum, Vol. 367, 1971, pp. 69-93.
[20] H. Yuan, S. Sarre, G. Ebinger and Y. Michotte, “Histological, Behavioural and Neurochemical Evaluation of Medial Forebrain Bundle and Striatal 6-OHDA Lesions as Rat Models of Parkinson’s Disease,” Journal of Neuroscience Methods, Vol. 144, No. 1, 2005, pp. 35-45.
[21] H. Thoenen and J. P. Tranzer, “Chemical Sympathectomy by Selective Destruction of Adrenergic Nerve Endings with 6-Hydroxydopamine,” Naunyn-Schmiedeberg’s Archives of Pharmacology, Vol. 261, No. 3, 1968, pp. 271-288.
[22] Y. Y. Glinka and M. B. Youdim, “Inhibition of Mitochondrial Complexes I and IV by 6-Hydroxydopamine,” European Journal of Pharmacology, Vol. 292, No. 3-4, 1995, pp. 329-332.
[23] M. J. Zigmond and E. M. Stricker, “Animal Models of Parkinsonism Using Selective Neurotoxins; Clinical and Basic Implications,” International Review of Neurobiology, Vol. 31, No. 1, 1989, pp. 2-60.
[24] E. M. Emborg, “Evaluation of Animal Models of Parkinson’s Disease for Neuroprotective Strategies,” Journal of Neuroscience Methods, Vol. 139, No. 2, 2004, pp. 121-143.
[25] T. Schallert and M. Woodlee, “Motor System: Orienting and Placing,” In: I. Q. Whishaw and B. Kolb, Eds., The Behaviour of the Laboratory Rat: A Handbook with Tests, Oxford University Press, New York, 2005, pp. 129-140.
[26] F. Curulli, A. Berry and E. Alleva, “Early Disruption of the Mother-Infant Relationship: Effects on Brain Plasticity and Implications for Psychopathology,” Neuroscience and Biobehavioral Reviews, Vol. 27, No. 1, 2003, pp. 73-82.
[27] B. A. Morrow, R. H. Roth, D. E. Redmond Jr., S. Diano and J. D. Elsworth, “Susceptibility to a Parkinsonian Toxin Varies during Primate Development,” Experimental Neurology, Vol. 235, No. 1, 2012, pp. 273-281.
[28] M. R. Gunnar, “Integrating Neuroscience and Psychological Approaches in the Study of Early Experiences,” Annals of the New York Academy of Sciences, Vol. 1008, No. 1, 2003, pp. 238-247.
[29] S. Hunot, F. Boissiere, B. Faucheux, B. Brugg, A. Mouatt-Prigent, Y. Agid and E. C. Hirsch, “Nitric Oxide Synthase and Neuronal Vulnerability in Parkinson’s Disease,” Neuroscience, Vol. 72, No. 2, 1996, pp. 355-363.
[30] P. K. Sonsalla, L. Y. Wong, S. L. Harris, J. R. Richardson, I. Khobahy, W. Li, B. S. Gadad and D. C. German, “Delayed Caffeine Treatment Prevents Nigral Dopamine Neuron Loss in a Progressive Rat Model of Parkinson’s Disease,” Experimental Neurology, Vol. 234, No. 2, 2012, pp. 482-487.
[31] J. F. Chen, K. Xu, J. P. Petzer, R. Staal, Y. H. Xu, M. Beilstein, P. K. Sonsalla, K. Castagnoli, N. Castagnoli Jr. and M. A. Schwarzschild, “Neuroprotection by Caffeine and A2A Adenosine Receptor Inactivation in a Model of Parkinson’s Disease,” The Journal of Neuroscience, Vol. 21, No. 10, 2001, p. 143.
[32] M. Morelli, A. R. Carta, A. Kachroo and M. A. Schwarzschild, “Pathophysiological Roles for Purines: Adenosine, Caffeine and Urate,” Progress in Brain Research, Vol. 183, 2010, pp. 183-208.
[33] J. S. Leinonen, J. Ahonen, K. Lönnrot, M. Jehkonen, P. Dastidar, G. Molnár and H. Alho, “Low Plasma Antioxidant Activity Is Associated with High Lesion Volume and Neurological Impairment in Stroke,” Stroke, Vol. 31, No. 1, 2000, pp. 33-39.
[34] K. Aoyama, N. Matsumura, M. Watabe, F. Wang, K. Kikuchi-Utsumi and T. Nakaki, “Caffeine and Uric Acid Mediate Glutathione Synthesis for Neuroprotection,” Neuroscience, Vol. 181, 2011, pp. 206-215.

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