Background: Traumatic brain injury (TBI) is posing serious health challenges for people across the globe due to high morbidity and mortality. However, none of the agents prevents or limits the damage caused by TBI because of its multifactorial etiology. Thus, the discovery of novel agents which can act via several pathways could serve the purpose and afford favorable consequence against TBI. Therefore, in the present article, we intended to investigate the protective effect of rhamnazin (RMZ), a dimethoxyflavone against experimentally induced TBI in mice. Methods: The effect of RMZ was investigated on cerebral edema and grip test score after induction of experimental brain injury in rats. The effect of RMZ was also investigated on neuronal degeneration in brain tissues of the experimental mice via Nissl staining and flow cytometry analysis. The expression of Bax and Bcl-2 was also quantified using Western blot analysis. The level of inflammatory cytokines (TNF-α and IL-1β) and oxidative stress markers (malondialdehyde, superoxide dismutase, and glutathione peroxidase) was also determined using enzyme-linked immunosorbent assay. Results: RMZ showed a significant reduction in edema and improved grip strength. It also prevented neuronal degeneration via inhibition of neuronal apoptosis as shown by flow cytometry analysis. RMZ showed an antiapoptotic effect via reduction of Bax and increased the expression of Bcl-2 in Western blot analysis. It also showed to inhibit oxidative stress and inflammation compared to the TBI group. Conclusion: Collectively, our study is first to demonstrate the protective effect of RMZ against experimentally induced TBI in rats.

1.
Werner
C
,
Engelhard
K
.
Pathophysiology of traumatic brain injury
.
Br J Anaesth
.
2007
;
99
(
1
):
4
9
. .
2.
Corrigan
JD
,
Selassie
AW
,
Orman
JA
.
The epidemiology of traumatic brain injury
.
J Head Trauma Rehabil
.
2010
;
25
(
2
):
72
80
. .
3.
Dixon
KJ
.
Pathophysiology of traumatic brain injury
.
Phys Med Rehabil Clin N Am
.
2017
;
28
(
2
):
215
25
. .
4.
Lee
S
.
Traumatic brain injury
.
Primary Management of Polytrauma
;
2019
. p.
19
31
. .
5.
Dewan
MC
,
Rattani
A
,
Gupta
S
,
Baticulon
RE
,
Hung
Y-C
,
Punchak
M
,
Estimating the global incidence of traumatic brain injury
.
J Neurosurg
.
2019
;
130
(
4
):
1080
97
. .
6.
Burda
JE
,
Bernstein
AM
,
Sofroniew
MV
.
Astrocyte roles in traumatic brain injury
.
Exp Neurol
.
2016
;
275
(
Pt 3
):
305
15
. .
7.
Corps
KN
,
Roth
TL
,
McGavern
DB
.
Inflammation and neuroprotection in traumatic brain injury
.
JAMA Neurol
.
2015
;
72
(
3
):
355
62
. .
8.
Rosenfeld
JV
,
Maas
AI
,
Bragge
P
,
Morganti-Kossmann
MC
,
Manley
GT
,
Gruen
RL
.
Early management of severe traumatic brain injury
.
Lancet
.
2012
;
380
(
9847
):
1088
98
. .
9.
Blennow
K
,
Brody
DL
,
Kochanek
PM
,
Levin
H
,
McKee
A
,
Ribbers
GM
,
Traumatic brain injuries
.
Nat Rev Dis Primers
.
2016
;
2
:
16084
. .
10.
Katz
L
,
Baltz
RH
.
Natural product discovery: past, present, and future
.
J Ind Microbiol Biotechnol
.
2016
;
43
(
2–3
):
155
76
. .
11.
Dias
DA
,
Urban
S
,
Roessner
U
.
A Historical overview of natural products in drug discovery
.
Metabolites
.
2012
;
2
(
2
):
303
36
. .
12.
Hashimoto
S
.
Natural product chemistry for drug discovery
.
J Antibiot
.
2011
;
64
(
10
):
697
.
13.
Bencheraiet
R
,
Kherrab
H
,
Kabouche
A
,
Kabouche
Z
,
Jay
M
.
Flavonols and antioxidant activity of ammi visnaga L. (apiaceae)
.
Rec Nat Prod
.
2011
;
5
(
1
):
52
5
.
14.
Zhang
L
,
Zhao
Z-X
,
Lin
C-Z
,
Zhu
C-C
,
Gao
L
.
Three new flavonol glycosides from Nervilia fordii
.
Phytochemistry Lett
.
2012
;
5
(
1
):
104
7
. .
15.
Martini
ND
,
Katerere
DR
,
Eloff
JN
.
Biological activity of five antibacterial flavonoids from Combretum erythrophyllum (Combretaceae)
.
J Ethnopharmacol
.
2004
;
93
(
2–3
):
207
12
. .
16.
Philchenkov
AA
,
Zavelevych
MP
.
Rhamnazin inhibits proliferation and induces apoptosis of human Jurkat leukemia cells in vitro
.
Ukr Biochem J
.
2015 Nov-Dec
;
87
(
6
):
122
8
. .
17.
Hawas
UW
,
Abou El-Kassem
LT
,
Shaher
F
,
Al-Farawati
R
.
In vitro inhibition of Hepatitis C virus protease and antioxidant by flavonoid glycosides from the Saudi costal plant Sarcocornia fruticosa
.
Nat Prod Res
.
2019
;
33
(
23
):
3364
71
. .
18.
Yu
Y
,
Cai
W
,
Pei
CG
,
Shao
Y
.
Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy
.
Biochem Biophys Res Commun
.
2015
;
458
(
4
):
913
9
. .
19.
Maas
AI
,
Stocchetti
N
,
Bullock
R
.
Moderate and severe traumatic brain injury in adults
.
Lancet Neurol
.
2008
;
7
(
8
):
728
41
. .
20.
Menon
DK
,
Schwab
K
,
Wright
DW
,
Maas
AI
.
Position statement: definition of traumatic brain injury
.
Arch Phys Med Rehabil
.
2010
;
91
(
11
):
1637
40
. .
21.
Fagerholm
ED
,
Hellyer
PJ
,
Scott
G
,
Leech
R
,
Sharp
DJ
.
Disconnection of network hubs and cognitive impairment after traumatic brain injury
.
Brain
.
2015
;
138
(
6
):
1696
709
. .
22.
Shukla
D
,
Devi
BI
,
Agrawal
A
.
Outcome measures for traumatic brain injury
.
Clin Neurol Neurosurg
.
2011
;
113
(
6
):
435
41
. .
23.
Katz
DI
,
Cohen
SI
,
Alexander
MP
.
Mild traumatic brain injury
.
Handb Clin Neurol
.
2015
;
127
:
131
56
. .
24.
Shin
SS
,
Dixon
CE
,
Okonkwo
DO
,
Richardson
RM
.
Neurostimulation for traumatic brain injury
.
J Neurosurg
.
2014
;
121
(
5
):
1219
31
. .
25.
Carney
N
,
Totten
AM
,
O’Reilly
C
,
Ullman
JS
,
Hawryluk
GW
,
Bell
MJ
,
Guidelines for the management of severe traumatic brain injury, fourth edition
.
Neurosurgery
.
2017
;
80
(
1
):
6
15
. .
26.
Donkin
JJ
,
Vink
R
.
Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments
.
Curr Opin Neurol
.
2010
;
23
(
3
):
293
9
. .
27.
Jha
RM
,
Kochanek
PM
,
Simard
JM
.
Pathophysiology and treatment of cerebral edema in traumatic brain injury
.
Neuropharmacology
.
2019
;
145
:
230
46
. .
28.
Papadopoulos
MC
,
Verkman
AS
.
Aquaporin-4 and brain edema
.
Pediatr Nephrol
.
2007
;
22
(
6
):
778
84
. .
29.
Winkler
EA
,
Minter
D
,
Yue
JK
,
Manley
GT
.
Cerebral edema in traumatic brain injury: pathophysiology and prospective therapeutic targets
.
Neurosurg Clin N Am
.
2016
;
27
(
4
):
473
88
. .
30.
Raghupathi
R
.
Cell death mechanisms following traumatic brain injury
.
Brain Pathol
.
2004
;
14
:
215
22
. .
31.
Stoica
BA
,
Faden
AI
.
Cell death mechanisms and modulation in traumatic brain injury
.
Neurotherapeutics
.
2010
;
7
(
1
):
3
12
. .
32.
Elmore
S
.
Apoptosis: a review of programmed cell death
.
Toxicol Pathol
.
2007
;
35
(
4
):
495
516
. .
33.
Czabotar
PE
,
Lessene
G
,
Strasser
A
,
Adams
JM
.
Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy
.
Nat Rev Mol Cell Biol
.
2014
;
15
(
1
):
49
63
. .
34.
Mukhopadhyay
S
,
Panda
PK
,
Sinha
N
,
Das
DN
,
Bhutia
SK
.
Autophagy and apoptosis: where do they meet?
Apoptosis
.
2014
;
19
(
4
):
555
66
. .
35.
Youle
RJ
,
Strasser
A
.
The BCL-2 protein family: opposing activities that mediate cell death
.
Nat Rev Mol Cell Biol
.
2008
;
9
(
1
):
47
59
. .
36.
García-Sáez
AJ
.
The secrets of the Bcl-2 family
.
Cell Death Differ
.
2012
;
19
(
11
):
1733
40
. .
37.
Cornelius
C
,
Crupi
R
,
Calabrese
V
,
Graziano
A
,
Milone
P
,
Pennisi
G
,
Traumatic brain injury: oxidative stress and neuroprotection
.
Antioxid Redox Signal
.
2013
;
19
(
8
):
836
53
. .
38.
Karve
IP
,
Taylor
JM
,
Crack
PJ
.
The contribution of astrocytes and microglia to traumatic brain injury
.
Br J Pharmacol
.
2016
;
173
(
4
):
692
702
. .
39.
Abdul-Muneer
PM
,
Chandra
N
,
Haorah
J
.
Interactions of oxidative stress and neurovascular inflammation in the pathogenesis of traumatic brain injury
.
Mol Neurobiol
.
2015
;
51
(
3
):
966
79
. .
40.
Dumitrescu
L
,
Popescu-Olaru
I
,
Cozma
L
,
Tulbă
D
,
Hinescu
ME
,
Ceafalan
LC
,
Oxidative stress and the microbiota-gut-brain axis
.
Oxid Med Cell Longev
.
2018
;
2018
:
2406594
. .
41.
Wu
G
,
Dai
X
,
Li
X
,
Jiang
H
.
Antioxidant and anti-inflammatory effects of rhamnazin on lipopolysaccharide-induced acute lung injury and inflammation in rats
.
Ajtcam
.
2017
;
14
(
4
):
201
12
. .
42.
Goyal
K
,
Yadav
R
.
Traumatic brain injury
. In:
Bidkar
PU
,
Vanamoorthy
P
, editors.
Acute neuro Care: focused approach to neuroemergencies
.
2020
. p.
139
58
.
43.
Kim
YJ
.
Rhamnazin inhibits LPS-induced inflammation and ROS/RNS in raw macrophages
.
J Nutr Health
.
2016
;
49
(
5
):
288
94
. .
44.
Yu
Y
,
Zhou
X-Z
,
Ye
L
,
Yuan
Q
,
Freeberg
S
,
Shi
C
,
Rhamnazin attenuates inflammation and inhibits alkali burn-induced corneal neovascularization in rats
.
RSC Adv
.
2018
;
8
(
47
):
26696
706
. .
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