Anti-edema effect of Aloe vera leaf extract following traumatic brain injury: Role of pro-inflammatory cytokines

Document Type : Original Research Article

Authors

1 Neuroscience Research Center, Department of Physiology, School of Medicine, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

2 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran. Department of Physiology and Pharmacology, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

3 Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran

4 Department of Psychology, Genetic Institute, Islamic Azad University- Zarand Branch, Kerman, Iran

5 Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran

Abstract

Objective: Based on anti-inflammatory effects of Aloe vera, the effect of aqueous extract of this plant on brain edema and changes in some pro-inflammatory cytokines was investigated after traumatic brain injury (TBI).
Materials and Methods: In this study, adult male Wistar rats were divided into 5 groups: Sham, TBI, vehicle (Veh), and low dose (LA) and high dose (HA) Aloe vera. The vehicle and aqueous extract of Aloe vera were injected intraperitoneally 30 min after induction of diffuse TBI by Marmarou’s method. Brain edema (brain water content), and transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6) and IL-1β levels in serum and brain were measured 24 hr after TBI induction.
Results: Increased brain edema by TBI was reduced by both LA and HA (p Aloe vera doses compared to Veh (p <0.001). The differences in the IL-6 serum levels among Veh, LA and HA groups were not significant. Increases in serum and brain IL-1β levels were reduced only in the HA group (p <0.001). Although only in the brain, TNF-α level increased after trauma, but both LA and HA inhibited it in a dose-dependent manner (p Conclusion: These results indicated that Aloe vera has a neuroprotective effect induced by reducing brain edema. The probable mechanism particularly for HA is decreasing levels of pro-inflammatory cytokines such as TGF-β, TNF-α, IL-6 and IL-1β.

Keywords


Abbas AK, Lichtman AH, Pillai S. 2014.
Cellular and molecular immunology Ebook: Elsevier Health Sciences, pp. 1-608.
Barzo P, Marmarou A, Fatouros P, Haysaki K,
Corwin F. 1997. Contribution of vasogenic
and cellular edema to traumatic brain
swelling measured by diffusion-weghted
imaging. J Neurosurg, 87: 900-907.
Benedı́J, Arroyo R, Romero C, Martıń
-Aragón
S, Villar AM. 2004. Antioxidant properties
and protective effects of a standardized
extract of Hypericum perforatum on
hydrogen peroxide-induced oxidative
damage in PC12 cells. Life Sci, 75:1263-
1276.
Benigni A, Cassis P, Remuzzi G. 2010.
Angiotensin II revisited: new roles in
inflammation, immunology and aging.
EMBO Mol Med, 2: 247-257.
Berger RP, Ta'Asan S, Rand A, Lokshin A,
Kochanek P. 2009. Multiplex assessment of
serum biomarker concentrations in wellappearing children with inflicted traumatic
brain injury. Pediatr Res, 65: 97-104.
Bibak B, Khaksari M, Badavi M, Rashidy-Pour
A. 2007. Effect of calcium channel blocker
nicardipine on brain edema in rats. Int J
Pharm, 5: 248-253.
Brough D, Tyrrell PJ, Allan SM. 2011.
Regulation of interleukin-1 in acute brain
injury. Trends Pharmacol Sci, 32: 617-622.
Bramlett HM, Furones-Alonso O, Lotocki G,
Rodriguez-Paez A, Sanchez-Molano J,
Keane RW. 2009. Sex differences in XIAP
cleavage after traumatic brain injury in the
rat. Neurosci Lett, 461: 49-53
Dalgard CL, Cole JT, Kean W, Lucky J,
Sukumar G, McMullen D. 2012. The
cytokine temporal profile in rat cortex after
controlled cortical impact. Front Mol
Neurosci, 5: 6-10.
Devaraj A, Karpagam T. 2011. Evaluation of
anti-inflammatory activity and analgesic
effect of Aloe vera leaf extract in rats. Int
Res J Pharm, 2: 103-110.
Duansak D ,Somboonwong J, Patumraj S.
2003. Effects of Aloe vera on leukocyte
adhesion and TNF‐α and IL‐6 levels in burn
wounded rats. Clin Hemorheol Microcir, 29:
239-246.
Eamlamnam K, Patumraj S, Visedopas N,
Thong-Ngam D. 2006. Effects of Aloe vera
and sucralfate on gastric microcirculatory
changes, cytokine levels and gastric ulcer
healing in rats. World J Gastroenterol,
12:2034-2039.
Gibson CL, Constantin D, Prior MJ, Bath PM,
Murphy SP. 2005. Progesterone suppresses
the inflammatory response and nitric oxide
synthase-2 expression following cerebral
ischemia. Experim Neurol, 193: 522-530.
Goodman JC, Robertson CS, Grossman RG,
Narayan RK. 1990. Elevation of tumor
necrosis factor in head injury. J
Neuroimmunol, 30: 213-217.
Guo Q, Sayeed I, Baronne LM, Hoffman SW,
Guennoun R, Stein DG. 2006. Progesterone
administration modulates AQP4 expression
and edema after traumatic brain injury in
male rats. Exp Neurol. 198: 469-478.
Habeeb F, Stables G, Bradbury F, Nong S,
Cameron P, Plevin R. 2007. The inner gel
component of Aloe vera suppresses
bacterial-induced pro-inflammatory
cytokines from human immune cells. Meth,
42: 388-393.
Hang C-h, Shi J-x, Tian J, Li J-s, Wu W, Yin
H-x. 2004. Effect of systemic LPS injection
on cortical NF-κB activity and inflammatory
response following traumatic brain injury in
rats. Brain Res, 1026: 23-32.
Hayakata T, Shiozaki T, Tasaki O, Ikegawa H,
Inoue Y, Toshiyuki F. 2004. Changes in
CSF S100B and cytokine concentrations in
early-phase severe traumatic bain injury.
Shock, 22:102-107.
Hyder AA, Wunderlich CA, Puvanachandra P,
Gururaj G, Kobusingye OC. 2007. The
impact of traumatic brain injuries: a global
perspective. Neuro Rehabilitation 22: 341-
353.
Intiso D, Zarrelli M, Lagioia G, Di Rienzo F,
Shahryari et al.
AJP, Vol. 11, No. 4, Jul-Aug 2021 392
De Ambrosio CC, Simone P. 2004. Tumor
necrosis factor alpha serum levels and
inflammatory response in acute ischemic
stroke patients. Neurol Sci, 24: 390-396.
Jafarzadeh H, Arabi M, Najafi N, Ahadi A.
2014. Effect of Aloe vera gel on TGF-β gene
expression in incisional skin wound in
BALB/c mice. J Gorgan Uni Med Sci, 16: 1-
10.
Jones N, Constantin D, Gibson CL, Prior M,
Morris P, Marsden C. 2004. A detrimental
role for nitric oxide synthase-2 in the
pathology resulting from acute cerebral
injury. J Neuropathol Exp Neurol, 63:708-
720.
Khaksari M, Ahmadi M, Najafipour H,
Shahrokhi N. 2014. Effect of Bunium
persicum aqueous extract plus endurance
exercise on cardiorespiratory capacity and
serum lipid profile. Avicenna J Phytomed,
4:118-125.
Khaksari M, Soltani Z, Shahrokhi N,
Moshtaghi G, Asadikaram G. 2010. The role
of estrogen and progesterone, administered
alone and in combination, in modulating
cytokine concentration following traumatic
brain injury. Can J Physiol Pharmacol, 89:
31-40.
Khaksari M, Mahmmodi R, Shahrokhi N,
Shabani M, Joukar S, Aqapour M. 2013. The
Effects of Shilajit on Brain Edema,
Intracranial Pressure and Neurologic
Outcomes following the Traumatic Brain
Injury in Rat. Iran J Basic Med Sci, 16: 858–
864.
Khaksari M, Abbasloo E, Dehghan f, Soltani Z,
Asadikaram Gh. 2015. The brain cytokine
levels are modulated by estrogen following
traumatic brain injury: Which estrogen
receptor serves as modulator? Int
Immunopharmacol, 28, 279-287.
Khaksari M, Keshavarzi Z, Gholamhoseinian
A, Bibak B. 2013. The effect of female
sexual hormones on the intestinal and serum
cytokine response after traumatic brain
injury: different roles for estrogen receptor
subtypes. Can J Physiol Pharmacol, 91:700-
707.
Keshavarzi Z, Khaksari M, Razmi Z, Soltani
Hekmat A, Naderi V, Rostami S. 2012. The
effects of cyclooxygenase inhibitors on the
brain inflammatory response following
traumatic brain injury in rats. Iran J Basic
Med Sci, 15: 1102-1105.
Keshavarzi Z, Rezapour TM, Vatanchian M,
Zare Hesari M, Nabizade Haghighi H,
Izanlu M, Sabaghian M, Shahveisi K. The
effects of aqueous extract of Aloe vera
leaves on the gastric acid secretion and brain
and intestinal water content following acetic
acid- induced gastric ulcer in male rats.
Avicenna J Phytomed, 4 : 137-143.
Kim KS, Wass C, Cross A, Opal S. 1992.
Modulation of blood-brain barrier
permeability by tumor necrosis factor and
antibody to tumor necrosis factor in the rat.
Lymphokine Cytokine Res, 11: 293-298.
Kovacs EJ. 2005. Aging, traumatic injury, and
estrogen treatment. Exp Gerontol, 40: 549-
555.
Kumar S, Singh BK, Pandey AK, Kumar A,
Sharma SK, Raj HG, et al.2007. A
chromone analog inhibits TNF-α induced
expression of cell adhesion molecules on
human endothelial cells via blocking NF-κB
activation. Bioorg Med Chem, 15: 2952-
2962.
Langmead L, Makins R, Rampton D. 2007.
Anti‐inflammatory effects of aloe vera gel in
human colorectal mucosa in vitro. Aliment
Pharmacol Ther, 19: 521-527.
Loane DJ, Faden AI. 2010. Neuroprotection for
traumatic brain injury: translational
challenges and emerging therapeutic
strategies. Trends Pharmacol Sci, 31: 596-
604.
Marmarou A, Fatouros PP, Barzó P, Portella G,
Yoshihara M, Tsuji O, et al.
2000.Contribution of edema and cerebral
blood volume to traumatic brain swelling in
head-injured patients. J Neurosurg. 93: 183-
193.
Mofid B, Soltani Z, Khaksari M, Shahrokhi N,
Nakhaee N, Karamouzian S, et al.2016.
What are the progesterone-induced changes
of the outcome and the serum markers of
injury, oxidant activity and inflammation in
diffuse axonal injury patients? Int
Immunopharmacol, 32: 103-110.
Morganti-Kossmann C, Semple B, Ziebell J,
Yan E, Bye N, Kossmann T. 2010.
Modulation of immune response by head
injury. New Insights to Neuroimmune
Biology: Elsevier, pp. 193-220.
Na'ama AS, Doron H, Horowitz M, Trembovler
V, Alexandrovich AG, Shohami E.
2007.Altered cytokine expression and
sustained hypothermia following traumatic
brain injury in heat acclimated mice. Brain
Res, 1185: 313-320.
Aloe vera affect pro-inflammatory cytokines
AJP, Vol. 11, No. 4, Jul-Aug 2021 393
Park M-Y, Kwon H-J, Sung M-K. 2011.
Dietary aloin, aloesin, or aloe-gel exerts
anti-inflammatory activity in a rat colitis
model. Life Sci, 88(: 486-492.
Park M-Y, Kwon H-J, Sung M-K. 2009.
Evaluation of aloin and aloe-emodin as antiinflammatory agents in aloe by using murine
macrophages. Biosci Biotechnol Biochem,
73: 828-832.
Prabjone R, Thong-Ngam D, Wisedopas N,
Chatsuwan T, Patumraj S. 2006. Antiinflammatory effects of Aloe vera on
leukocyte–endothelium interaction in the
gastric microcirculation of Helicobacter
pylori-infected rats. Clin Hemorheol
Microcir, 35: 359-366.
Rancan M, Otto VI, Hans VH, Gerlach I, Jork
R, Trentz O, et al. 2001. Upregulation of
ICAM 1 and MCP 1 but not of MIP 2 and
sensorimotor deficit in response to traumatic
axonal injury in rats. J Neurosci Res, 63:
438-446.
Rothwell N. 2003. Interleukin-1 and neuronal
injury: mechanisms, modification, and
therapeutic potential. Brain Behav Immun,
17:152-157.
Sarkaki AR, Khaksari Haddad M, Soltani Z,
Shahrokhi N, Mahmoodi M . 2013. Timeand dose-dependent neuroprotective effects
of sex steroid hormones on inflammatory
cytokines after a traumatic brain injury. J
Neurotrauma, 30:47-54.
Sarkar D, Dutta A, Das M, Sarkar K, Mandal C,
Chatterjee M. 2005. Effect of Aloe vera on
nitric oxide production by macrophages
during inflammation. Indian J pharmacol,
37:371-376.
Shahrokhi N, Haddad MK, Joukar S, Shabani
M, Keshavarzi Z, Shahozehi B. 2012.
Neuroprotective antioxidant effect of sex
steroid hormones in traumatic brain injury.
Pak J Pharm Sci, 25: 219-225.
SM, Fan L, Faden AI. 1999. Early neuronal
expression of tumor necrosis factor-α after
experimental brain injury contributes to
neurological impairment. J Neuroimmunol,
95:115-125.
Soltani Z, Khaksari M, Jafari E, Iranpour M,
Shahrokhi N. 2015. Is genistein
neuroprotective in traumatic brain injury?
Physiol Behav, 152: 26-31.
Stein DM, Lindell A, Murdock KR, Kufera JA,
Menaker J, Keledjian K, et al. 2011.
Relationship of serum and cerebrospinal
fluid biomarkers with intracranial
hypertension and cerebral hypoperfusion
after severe traumatic brain injury. J Trauma
Acute Care Surg, 70:1096-1103.
Taupin V, Toulmond S, Serrano A, Benavides
J, Zavala F. 1993. Increase in IL-6, IL-1 and
TNF levels in rat brain following traumatic
lesion: influence of pre-and post-traumatic
treatment with Ro5 4864, a peripheral-type
(p site) benzodiazepine ligand. J
Neuroimmunol, 42: 85-91.
Valkonen T, Martikainen P, Blomgren J. 2004.
Increasing excess mortality among nonmarried elderly people in developed
countries. Demogr Res, 2: 305-330.
Woodcock T, Morganti-Kossmann C. 2013.
The role of markers of inflammation in
traumatic brain injury. Front Neurol, 4:18-
27.
Woodroofe M, Sarna G, Wadhwa M, Hayes G,
Loughlin A, Tinker A, et al. 1991. Detection
of interleukin-1 and interleukin-6 in adult rat
brain, following mechanical injury, by in
vivo microdialysis: evidence of a role for
microglia in cytokine production. J
Neuroimmunol, 33: 227-236.
Yun N, Lee C-H, Lee S-M. 2009. Protective
effect of Aloe vera on polymicrobial sepsis
in mice. Food Chem Toxicol, 47: 1341-
1348.