The effects of inosine on clinical and histological findings after experimental spinal cord injury in rats

https://doi.org/10.17221/8106-VETMEDCitation:Ledecky V., Kuricova M., Liptak T., Cizkova D. (2015): The effects of inosine on clinical and histological findings after experimental spinal cord injury in rats. Veterinarni Medicina, 60: 186-193.
download PDF
Inosine is a naturally occurring purine nucleoside, the effect of which was discovered only in recent decades. It has potential to prevent neuronal and glial death and can stimulate axonal outgrowth. This study evaluated the effect of inosine (400 mg per rat) administered orally two hours after experimental spinal cord injury and continuously daily for 12 days. We observed the effect of inosine on clinical and histological changes by means of measurement of recovery of hind leg motor function and urinary bladder function, frequency of spasms, neuronal profile and spinal cord tissue sparing. The rats were randomly divided into three groups, SCI-Aqua and SCI-Inosine, with daily administration of aqua for injection or inosine, and SCI-Sham group without spinal injury. The motor function of hind legs and urinary bladder function were evaluated daily for 12 days after the spinal cord injury. In the SCI-Inosine group we recorded lower incidence of spasms due to spinal cord irritation in the early postoperative period when compared to the SCI-Aqua group. We used immunohistochemistry with specific neuronal antibodies to determine the neuronal profiles and the Luxol fast blue staining method to detect the white and grey matter tissue sparing. In our study we recorded significant differences in recovery between the SCI-Aqua and SCI-Inosine group from eighth days after surgery. Moreover, the post mortem investigation of transverse spinal cord sections revealed significantly higher numbers in the SCI-Inosine group (more neurons, greater tissue sparing). According to our findings inosine accelerates the recovery of neurological functions.
References:
BASSO D. MICHELE, BEATTIE MICHAEL S., BRESNAHAN JACQUELINE C. (1995): A Sensitive and Reliable Locomotor Rating Scale for Open Field Testing in Rats. Journal of Neurotrauma, 12, 1-21  https://doi.org/10.1089/neu.1995.12.1
 
BEATTIE MICHAEL S., FAROOQUI AKHLAQ A., BRESNAHAN JACQUELINE C. (2000): Review of Current Evidence for Apoptosis After Spinal Cord Injury. Journal of Neurotrauma, 17, 915-925  https://doi.org/10.1089/neu.2000.17.915
 
Benowitz L. I., Goldberg D. E., Madsen J. R., Soni D., Irwin N. (1999): Inosine stimulates extensive axon collateral growth in the rat corticospinal tract after injury. Proceedings of the National Academy of Sciences, 96, 13486-13490  https://doi.org/10.1073/pnas.96.23.13486
 
Bohnert Debra M., Purvines Scott, Shapiro Scott, Borgens Richard B. (2007): Simultaneous Application of Two Neurotrophic Factors after Spinal Cord Injury. Journal of Neurotrauma, 24, 846-863  https://doi.org/10.1089/neu.2006.0101
 
Coates Joan R. (2000): Intervertebral Disk Disease. Veterinary Clinics of North America: Small Animal Practice, 30, 77-110  https://doi.org/10.1016/S0195-5616(00)50004-7
 
Conta A C, Stelzner D J (): Immunomodulatory effect of the purine nucleoside inosine following spinal cord contusion injury in rat. Spinal Cord, 46, 39-44  https://doi.org/10.1038/sj.sc.3102057
 
Fawcett James W. (2006): Overcoming Inhibition in the Damaged Spinal Cord. Journal of Neurotrauma, 23, 371-383  https://doi.org/10.1089/neu.2006.23.371
 
Fawcett James W, Asher Richard.A (1999): The glial scar and central nervous system repair. Brain Research Bulletin, 49, 377-391  https://doi.org/10.1016/S0361-9230(99)00072-6
 
Fehlings Michael G., Tator Charles H., Linden R. Dean (1989): The effect of nimodipine and dextran on axonal function and blood flow following experimental spinal cord injury. Journal of Neurosurgery, 71, 403-416  https://doi.org/10.3171/jns.1989.71.3.0403
 
Gomez G. (2003): Differential requirement for A2a and A3 adenosine receptors for the protective effect of inosine in vivo. Blood, 102, 4472-4478  https://doi.org/10.1182/blood-2002-11-3624
 
Haskó György, Sitkovsky Michail V., Szabó Csaba (2004): Immunomodulatory and neuroprotective effects of inosine. Trends in Pharmacological Sciences, 25, 152-157  https://doi.org/10.1016/j.tips.2004.01.006
 
Haskó György, Linden Joel, Cronstein Bruce, Pacher Pál (2008): Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nature Reviews Drug Discovery, 7, 759-770  https://doi.org/10.1038/nrd2638
 
Jurkowitz Marianne S., Litsky Monica L., Browning Megan J., Hohl Charlene M. (1998): Adenosine, Inosine, and Guanosine Protect Glial Cells During Glucose Deprivation and Mitochondrial Inhibition: Correlation Between Protection and ATP Preservation. Journal of Neurochemistry, 71, 535-548  https://doi.org/10.1046/j.1471-4159.1998.71020535.x
 
Lee Y.-S., Lin C.-Y., Jiang H.-H., DePaul M., Lin V. W., Silver J. (): Nerve Regeneration Restores Supraspinal Control of Bladder Function after Complete Spinal Cord Injury. Journal of Neuroscience, 33, 10591-10606  https://doi.org/10.1523/JNEUROSCI.1116-12.2013
 
Li G. L., Farooque Mohammad, Holtz Anders, Olsson Yngve (1999): Apoptosis of oligodendrocytes occurs for long distances away from the primary injury after compression trauma to rat spinal cord. Acta Neuropathologica, 98, 473-480  https://doi.org/10.1007/s004010051112
 
Litsky Monica L, Hohl Charlene M, Lucas Jen H, Jurkowitz Marianne S (1999): Inosine and guanosine preserve neuronal and glial cell viability in mouse spinal cord cultures during chemical hypoxia. Brain Research, 821, 426-432  https://doi.org/10.1016/S0006-8993(99)01086-0
 
Liu F, You SW, Yao LP, Liu HL, Jiao XY, Shi M, Z1hao QB, Ju G (2006): Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 44, 421–426.
 
Liu Fei, Yao Liping, Yuan Jianlin, Liu Heliang, Yang Xiaojian, Qin Weijun, Wu Guojun, Yang Lijun, Wang He, Takahashi Norio, Yamaguchi Osamu (2009): Protective Effects of Inosine on Urinary Bladder Function in Rats With Partial Bladder Outlet Obstruction. Urology, 73, 1417-1422  https://doi.org/10.1016/j.urology.2008.10.032
 
Markowitz Clyde E., Spitsin Sergei, Zimmerman Vanessa, Jacobs Dina, Udupa Jayaram K., Hooper D. Craig, Koprowski Hilary (2009): The Treatment of Multiple Sclerosis with Inosine. The Journal of Alternative and Complementary Medicine, 15, 619-625  https://doi.org/10.1089/acm.2008.0513
 
Mautes AEM, Weinzierl MR, Donovan F, Noble LJ (2000): Vascular events after spinal cord injury: Contribution to secondary pathogenesis. Physical Therapy 80, 673–687.
 
McKee WM (1990): Spinal trauma in dogs and cats: A review of 51 cases. Veterinary Record 26, 285–289.
 
Mubagwa K (): Adenosine, adenosine receptors and myocardial protection An updated overview. Cardiovascular Research, 52, 25-39  https://doi.org/10.1016/S0008-6363(01)00358-3
 
Park Edward H., White George A., Tieber Lisa M. (2012): Mechanisms of injury and emergency care of acute spinal cord injury in dogs and cats. Journal of Veterinary Emergency and Critical Care, 22, 160-178  https://doi.org/10.1111/j.1476-4431.2012.00723.x
 
Petrausch B, Tabibiazar R, Roser T, Jing Y, Goldman D, Stuermer CAO, Irwin N, Benowitz LI (2000): A purine-sensitive pathway regulates multiple genes involved in axon regeneration in goldfish retinal ganglion cells. Journal of Neuroscience 20, 8031–8041.
 
Pope Malcolm H., Goh Kheng Lim, Magnusson Marianne L. (2002): S PINE E RGONOMICS. Annual Review of Biomedical Engineering, 4, 49-68  https://doi.org/10.1146/annurev.bioeng.4.092101.122107
 
Schwab Martin E (2004): Nogo and axon regeneration. Current Opinion in Neurobiology, 14, 118-124  https://doi.org/10.1016/j.conb.2004.01.004
 
Sherwood AM, Graves DE, Priebe MM (2000): Altered motor control and spasticity after spinal cord injury: Subjective and objective assessment. Journal of Rehabilitation Research and Development 37, 41–52.
 
Tator Charles H., Koyanagi Izumi (1997): Vascular mechanisms in the pathophysiology of human spinal cord injury. Journal of Neurosurgery, 86, 483-492  https://doi.org/10.3171/jns.1997.86.3.0483
 
Vanický Ivo, Urdzíková Lucia, Saganová Kamila, Čízková Dáša, Gálik Ján (2001): A Simple and Reproducible Model of Spinal Cord Injury Induced by Epidural Balloon Inflation in the Rat. Journal of Neurotrauma, 18, 1399-1407  https://doi.org/10.1089/08977150152725687
 
Wakai A., Winter Desmond C., Street John T., O'Sullivan Ronan G., Wang Jiang H., Redmond H.Paul (2001): Inosine Attenuates Tourniquet-Induced Skeletal Muscle Reperfusion Injury. Journal of Surgical Research, 99, 311-315  https://doi.org/10.1006/jsre.2001.6192
 
Webb AA, Ngan S, Fowler D (2010): Spinal cord injury. II: Prognostic indicators, standards of care and clinical trials. Canadian Veterinary Journal 51, 598–604.
 
Wu Zhongliang, Liu Fei, Wang Yazhou, Jiao Xiying, Shi Ming, Zhao Qingbo, Ju Gong, You Siwei (2008): Reduced cell death by inosine pretreatment after photochemically induced cerebral ischemia in adult rats. Progress in Natural Science, 18, 1513-1518  https://doi.org/10.1016/j.pnsc.2008.03.032
 
Yu W. (2006): Adenosine receptor expression and function in bladder uroepithelium. AJP: Cell Physiology, 291, C254-C265  https://doi.org/10.1152/ajpcell.00025.2006
 
Zai L., Ferrari C., Subbaiah S., Havton L. A., Coppola G., Strittmatter S., Irwin N., Geschwind D., Benowitz L. I. (): Inosine Alters Gene Expression and Axonal Projections in Neurons Contralateral to a Cortical Infarct and Improves Skilled Use of the Impaired Limb. Journal of Neuroscience, 29, 8187-8197  https://doi.org/10.1523/JNEUROSCI.0414-09.2009
 
Zai L., Ferrari C., Dice C., Subbaiah S., Havton L. A., Coppola G., Geschwind D., Irwin N., Huebner E., Strittmatter S. M., Benowitz L. I. (): Inosine Augments the Effects of a Nogo Receptor Blocker and of Environmental Enrichment to Restore Skilled Forelimb Use after Stroke. Journal of Neuroscience, 31, 5977-5988  https://doi.org/10.1523/JNEUROSCI.4498-10.2011
 
download PDF

© 2020 Czech Academy of Agricultural Sciences | Prohlášení o přístupnosti