SYSTEMATIC REVIEW OF RECOVERY OF SPINAL CORD INJURY WITH ANTIOXIDANT THERAPY

KOFF, MARCO ANTONIO EDUARDO; AJIBOYE, LUKMAN OLALEKAN; LISBOA, NATÁLIA DIEL; FALAVIGNA, ASDRUBAL

doi:10.1590/S1808-1851201716011171639

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SYSTEMATIC REVIEW ARTICLE • Coluna/Columna 16 (1) • Jan-Mar 2017 • https://doi.org/10.1590/S1808-1851201716011171639 copy

SYSTEMATIC REVIEW OF RECOVERY OF SPINAL CORD INJURY WITH ANTIOXIDANT THERAPY

REVISÃO SISTEMÁTICA DA RECUPERAÇÃO DE TRAUMA RAQUIMEDULAR COM TERAPIA ANTIOXIDANTE

REVISIÓN SISTEMÁTICA DE RECUPERACIÓN DE TRAUMA RAQUIMEDULAR CON TERAPIA ANTIOXIDANTE

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

The objective of the paper is to analyze the frequency and efficacy of experimental studies with antioxidant therapy. A search was conducted in the pubmed.gov database using the keywords "antioxidants" AND "spinal cord injury", from January 2000 to December 2015, resulting in 686 articles. Studies of non-traumatic injuries, non-antioxidant therapies, absence of neurological and functional evaluation, and non-experimental studies were excluded, leaving a total of 43 articles. The most used therapies were melatonin (16.2%), quercetin (9.3%), epigallocatechin and edaravone (6.9%). The most frequent route of administration was intraperitoneal (72.09%). The dose and mode of administration varied greatly, with a single dose being the most commonly used (39.53%). The time elapsed from trauma to treatment was 0-15 minutes (41.8%), 15-60 minutes (30%) and over 60 minutes (10.6%). Histological analysis was performed in 32 studies (74.41%). The BBB scale was the main functional measure applied (55.8%), followed by the inclined plane test (16.2%) and the Tarlov scale (13.9%). Positive outcomes were observed in 37 studies (86.04%). The heterogeneity of antioxidant therapy, with different types, doses, and measurements observed, limits the comparison of efficacy. Standardized protocols are required to make clinical translation possible.

Keywords:
Antioxidants; Spinal cord injuries; Neurology; Neurosurgery; Review

Author	Antioxidant theraphy	Mechanism of action	Posology	Administration mode	Elapsed time from SCI to therapy	Functional recovery measurement
Cemil, et al. (2012)¹³	Aged Garlic Extract	Antioxidant proprieties, molecular mechanism uncertain	250 mg/kg	Oral	24 hour	Inclinated Plane Test, Histology
Kotil, et al. (2006)¹⁴	Agmatine	Inhibits enzime iNOS	50 mg/kg ou 100mg/kg	Intraperitoneal	5 minutes	Tarlov Neurological Scale, Inclinated Plane Test
Toklu, et al. (2010)¹⁵	Alpha-Lipoic Acid	Co-factor for several mitochondrial dehydrogenases, participates in redox reactions.	50 mg/kg	Intraperitoneal	30 minutes	Gale Motor Fuctional Scale, Histology
Sayin, et al. (2013)¹⁶	Alpha-Lipoic Acid	50, 100, 150, 200 mg/kg	Intraperitoneal	Immediately	BBB†, Inclinated Plane Test, Histology
Al Jadid, et al. (2009)¹⁷	Alpha-Tocopherol	Endogenous antioxidant and reduces lipid peroxidation and generation of free radicals	1000mg/kg and 2000mg/kg	Oral	Not Specified	Behavior Test
Asirvatham, et al. (2012)¹⁸	Alpha-Tocopherol	2,000 mg/kg	Intraperitoneal	Not Specified	BBB†
Soy, et al. (2004)¹⁹	Aminoguanidine	High-potency iNOS inhibitor	100mg/kg	Intraperitoneal	Immediately	Inclinated Plane Test, Tarlov Neurological Scale, Histology
Moon, et al. (2012)²⁰	Angelica Dahuricae	Inhibits LPS- induced expression of inflammatory mediators such as NO, inducible nitric oxide synthase (iNOS), COX-2, and TNF-alpha in macrophages by inhibiting MAPKsand IkB/NF-kB signal pathways.	100mg/kg	Oral	2 hour	Inclinated Plane Test, Foot Print Test, Histology
Kim, et al. (2011)²¹	Anthocyanin	As antioxidant efects, inhibit inflammation, as a scavenger of active oxygen species	400 mg/kg	Via NG-tube	Not Specified	BBB†, Histology
Zhang, et al. (2014)²²	Apigenin	Anti-oxidant through inhibition of NADPH-oxidase enzyme	10 mg/kg and 20 mg/kg	Intraperitoneal	Immediately	BBB†
Impellizzeri, et al. (2011)²³	Apocynin	5mg/kg 10% DMSO	Intraperitoneal	1 hour	Neurological Examination, Histology
Yan, et al. (2014)²⁴	Ascorbic Acid	Free Radical Scavenger	100mg/kg 200mg/kg	Intraperitoneal	1 hour	BBB†, Foot Print Test, Histology
Wang, et al. (2014)²⁵	Curcumin	Inhibition of NF-kB and JAK2/STAT3 pathways, decreases levels of IL-1 e NO.	50mg/kg	Intraperitoneal	Not Specified	BMS Scale, Histology
Kim, et al. (2014) ²⁶	Curcumin	200mg/kg	Intraperitoneal	Not Specified	BBB†, Histology
Kalayci, et al. (2005)²⁷	Ebselen	Glutatione-related mechanism, still uncertain	10mg/kg	Intraperitoneal	Immediately	Inclinated Plane Test, Neurological Examination, Histology
Ozgiray, et al. (2011)²⁸	Edaverone	Inhibitory effect on lipid peroxidation by scavenging free radicals, and it prevents vascular endothelial cell injury	3 mg/kg	Intraperitoneal	1 hour	Tarlov Neurological Scale
Wang, et al. (2013)²⁹	Edaverone	5mg/kg	Intraperitoneal	5 minutes	BBB†, Histology
Otha, et al. (2005)³⁰	Edaverone	5mg/kg	Endovenous	5 minutes	BBB†, Histology
Khalatbary, et al. (2009) ³¹	Epigallocatechin Gallate	Act in inflammation and apoptosis, uncert	50/kg	Intraperitoneal	Immediately	Behavior Test, Histology
Tian, et al. (2013)³²	Epigallocatechin Gallate	20mg/kg	Intrathecal	Immediately	BBB†, Histology
Genovese, et al. (2007)³³	Melatonin	Free radical scavenger, stimules catalase, SOD, GSH- reductase, peroxidase. Decreases lipid peroxidation.	10mg/kg	Intraperitoneal	1 hour	BBB†, Histology
Schiaveto-de-Souza, et al. (2013)³⁴	Melatonin	2.5mg/kg	Intraperitoneal	5 min prior SCI and 1h after	BBB†
Park, et al. (2012)³⁵	Melatonin	10 mg/kg	Subcutaneous	24 hour	BBB†
Gul, et al. (2005)³⁶	Melatonin	50mg/kg; 100mg/kg	Intraperitoneal	Immediately	Inclinated Plane Test, Neurological Examination, Histology
Genovese, et al (2005)³⁷	Melatonin	50mg/kg	Intraperitoneal	30 minutes	Tarlov Neurological Scale, Histology
Cayli, et al. (2004)³⁸	Melatonin	10mg/kg	Intraperitoneal	Immediately	Gale Motor Fuctional Scale, Eletrophysiology
Fujimoto, et al. (2000)³⁹	Melatonin	2,5mg/kg	Intraperitoneal	5 minutes	Tarlov Neurological Scale, Inclinated Plane Test, Histology
Fee, et al. (2010)⁴⁰	Melatonin Analogue	10mg/kg and 100mg/kg	Intraperitoneal	15 minutes	Behavior Test, Histology
Liu, et. Al. (2013)⁴¹	Mn (III) Tetrakis	Potentializes SOD activity and scavengers ROS	4 mg/kg	Intrathecal	Immediately	BBB†, Histology
Hillard, et al. (2004)⁴²	Tempol	Stimulate SOD catalytic activity, also inhibits hydroxyl radical generation by oxidizing transition metals necessary for Haber-Weiss/Fenton reactions.	69mg/kg, 138mg/kg, 275mg/kg, 550mg/kg	Intraperitoneal	20 minutes	BBB†, Histology
Ling, et al. (2013)⁴³	Mn (III) Tetrakis	Potentializes SOD activity and scavengers ROS	10mg/kg	Intraperitoneal	1 hour	Histology
Cavus, et al. (2014)⁴⁴	Montelukast	Leukotrien receptor antago- nist that specifically inhibites sodium cisteinyl leukotrien CysLT1 receptor, diminishing inflammatory process	5mg/kg	Intraperitoneal	Immediately	Tarlov Neurological Scale, Histology
Kanter, et al. (2006)⁴⁵	Nigella Sativa	Anti-inflammatory, immunomodulatory	0,2ml/kg	Intraperitoneal	Immediately	Inclinated Plane Test, Neurological Examination, Histology
Assis, et al. (2014)⁴⁶	Proantrocyanidin	Stimulates SOD, inhibits NDMA glutamate receptors	10/mg/kg	Intraperitoneal	1 hour	BBB†, Grip Force Test
Schultke, et al. (2010)⁴⁷	Quercitin	Scavenger, decreases lipid peroxidation	25mmol/kg	Intraperitoneal	1 hour	BBB†, Histology
Song, et al. (2013)⁴⁸	Quercitin	0,2mg/kg	Intraperitoneal	1 hour	BBB†, Histology
Schultke, et al. (2003)⁴⁹	Quercitin	5, 25, 50, 100 mmol/kg	Intraperitoneal	1 hour	BBB†, Histology
Genovese, et al. (2006)⁵⁰	Quercitin	30mg/kg	Oral	1 hour	BBB†, Histology
Ates, et al. (2006)⁵¹	Resveratrol	Anti-oxidation effect, suppression of immunoreactivity, reduction of inflammatory cytokines including IL-1β, IL-10, TNF-α, and myeloperoxidase, inhibition of injury-induced apoptosis	100mg/kg	Intraperitoneal	24h	Motor Function Score, Inclinated Plane Test, Histology
Liu, et. Al. (2011)⁵²	Resveratrol	200mg/kg	Intraperitoneal	Not Specified	BBB†, Behavior Test,Locomotor Rating Scale, Histology
Yune, et al. (2009)⁵³	Scutellaria Baicalensis	Inhibition lipopolysaccharide-induced expression and anti-inflammatory proprieties	30, 100, or 300 mg/kg	Oral	2 hour	BBB†, Footprint Test, Histology
Sharma, et al. (2006)⁵⁴	Sintetic (H-29051)	Melatonin Analogue	50mg/kg	Via NG-tube	10 minutes	Inclinated Plane Test, Histology
Serarslan, et al. (2010)⁵⁵	Tadalafil	Aa selective inhibitor of cyclic guanosine monophosphate (cGMP)-speciﬁc phosphodiesterase type 5	2 mg/kg	Via NG-tube	Immediately	Neurological Examination

Variable	Number of articles	%
Antioxidant
Melatonin	7	16.2
Quercitin	4	9.3
Epigalloccatecin	3	6.9
Edaverone	3	6.9
Resveratrol	2	4.6
Curcumin	2	4.6
Alpha-Licoic Acid	2	4.6
Other*	20	46.5
Administration mode
Intraperitoneal	31	72
Oral/Nasogastric Tube	8	18.6
Intrathecal	2	4.6
Subcutaneous	1	2.3
Intravenous	1	2.3
Total dosage
1 Dose	17	39.5
2 Doses	6	13.9
3 Doses	3	6.9
4 Doses	2	4.6
5 Doses	1	2.3
7 Doses	4	9.3
> 7 doses	9	20.9
Functional recovery
BBB†	24	55.8
Inclinated Plain Test	7	16.2
Modified Tarlov Scale	6	13.9
Other	6	13.9
Elapsed time trauma to therapy
0-15 minutes	18	41.8
15 min - 30 min	3	6.9
30 min - 60 min	10	23.2
> 60 min	5	11.6
Not Specified	6	13.9
Time of observation
< 1 week	14	32.5
1 week - 2 weeks	6	13.9
2 weeks - 3 weeks	8	18.6
3 weeks - 4 weeks	2	4.6
4 weeks	6	13.9
> 4 weeks	5	11.6
Not specified	2	4.6

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