Received: 10 April 2019 | Accepted: 23 August 2019

DOI: 10.1002/jcp.29173

REVIEW ARTICLE

Modulation of autophagy in traumatic brain injury

Zhiqing Zeng1* | Yao Zhang2* | Weiping Jiang1 | Lu He1 | Hongtao Qu1

1
Department of Neurosurgery, First Affiliated
Hospital, University of South China, Abstract
Hengyang, China Traumatic brain injury (TBI) is defined as a traumatically induced structural injury or
2
Department of Clinical Laboratory, The First
physiological disruption of brain function as a result of external forces, leading to
People’s Hospital of Changde City, Changde
City, Hunan Province, China adult disability and death. A growing body of evidence reveals that alterations in
autophagy‐related proteins exist extensively in both experimentally and clinically
Correspondence
Lu He and Hongtao Qu, Department of after TBI. Of note, the autophagy pathway plays an essential role in pathophysio-
Neurosurgery, First Affiliated Hospital,
logical processes, such as oxidative stress, inflammatory response, and apoptosis, thus
University of South China, 421001
Hengyang, China. contributing to neurological properties of TBI. With this in mind, this review
Email: luhe1989@126.com (L. H.) and
summarizes a comprehensive overview on the beneficial and detrimental effects of
qht959801@sina.com (H. Q.)
autophagy in pathophysiological conditions and how these activities are linked to the
Funding information
pathogenesis of TBI. Moreover, the relationship between oxidative stress, inflamma-
Heath and Family Planning Commission
Science Foundation Projects of Hunan tion, apoptosis, and autophagy occur TBI. Ultimately, multiple compounds and various
Province of China, Grant/Award Number:
drugs targeting the autophagy pathway are well described in TBI. Therefore,
C20190121; National Natural Science
Foundation of Hunan, Grant/Award Number: autophagy flux represents a potential clinical therapeutic value for the treatment of
2018JJ6070; Technology and Innovation
TBI and its complications.
Guiding Program of Hunan, Grant/Award
Number: 2017SK50207; National Natural
Science Foundation of China, Grant/Award KEYWORDS
Number: 81803535 apoptosis, autophagy, inflammatory response, oxidative stress, traumatic brain injury

1 | INTRODUCTION patients’ outcomes. TBI triggers a cascade of pathophysiological

Traumatic brain injury (TBI) remains a significant worldwide medical
concern as a considerable cause of death and permanent disability
among adults, imposing public burden in modern society (Langlois,
Rutland‐Brown, & Wald, 2006). TBI is recognized as penetrating or
blunt trauma and nonaccidental head injury with traumatic etiology.
The pathological process of TBI is very complicated and is generally
divided into two phases, primary brain injury and secondary brain
injury. The primary brain injury is the major factor in determining the
actions by secondary brain injury, such as oxidative stress,
inflammatory response, and apoptosis, resulting in neuronal cell
death, brain edema, and neurological deficits. The development of
neurological deficits includes learning and memory impairments,
brain damage, and motor behavioral functions (Saatman et al., 2008).
But no effective therapies for patients with TBI in clinical interven-
tion currently exist. Thus, understanding the pathophysiological
processes after TBI, and identifying potential therapeutic approaches
are urgently needed and are of great importance.

Abbreviations: 17‐AAG, 17‐Allylamino‐demethoxygeldanamycin; 3‐MA, 3‐Methyladenine; 3‐MST, 3‐Mercaptopyruvate sulfurtransferase; ALI, Acute lung injury; ALS, Amyotrophic lateral
sclerosis; ANDRO, Andrographolide; BBB, Blood–brain barrier; BMSCs, Bone marrow stromal cells; BNIP3L, Bcl‐2/E1B‐19K‐interacting protein 3‐like; CCI, Controlled cortical impact; CL,
Cardiolipin; CQ, Chloroquine; CR, Caloric restriction; CTX, Ceftriaxone; CXs, Connexins; DHA, Docosahexaenoic acid; EPPS, 4‐(2‐Hydroxyethyl)‐1‐piperazinepropanesulphonic acid; ERK,
Extracellular signal‐regulated kinase; FGF2, Fibroblast growth factor‐2; FoxO, Forkhead box; GCEE, c‐Glutamylcysteinyl ethyl ester; H2S, Hydrogen sulfide; HO‐1, heme oxygenase‐1; IL‐33,
Interleukin‐33; JNK, c‐Jun NH2‐terminal kinase; LC3, Microtubule‐associated protein light chain 3; LKE, Lanthionine ketimine ethyl ester; Lut, Luteolin; MB, Methylene blue; Mdivi‐1,
Mitochondrial division inhibitor 1; Melatonin, N‐acetyl‐5‐methoxytryptamine; miRNAs, MicroRNAs; MSCs‐IL‐10, Mesenchymal stem cells overexpressing interleukin10; NEC‐1, Necrostatin‐1;
NLRP3, NOD‐like receptor protein‐3; NR2B, N‐methyl‐d‐aspartate receptor 2B; Nrf2, Nuclear factor‐erythroid2‐like2; P188, Poloxamer 188; P2X7R, P2X7 receptor; p62, SQSTM1/p62; PEA,
Palmitoylethanolamide; PG, Progesterone; PQQ, Pyrroloquinoline quinone; RSG, Rosiglitazone; RV, Resveratrol; STING, Stimulator of interferon genes; TAK‐242, Resatorvid; TAT, Trans‐
activating transduction protein; TBI, Traumatic brain injury; THC, Tetrahydrocurcumin; TLR4, Toll‐like receptor 4; TPEN, Zinc chelator N,N,N’,N’‐tetrakis‐ (2‐pyridylmethyl) ethylenediamine;
UCH‐L1, Ubiquitin carboxy‐terminal hydrolase L1; VPA, Valproic acid; ω‐3 PUFA, Omega‐3 polyunsaturated fatty acids.

*Zhiqing Zeng and Yao Zhang contributed equally to this work.

J Cell Physiol. 2019;1–13. wileyonlinelibrary.com/journal/jcp © 2019 Wiley Periodicals, Inc. | 1

2 |
The term autophagy referred to as “self‐eating,” is an evolutio-
narily conserved process in which cells mediate the degradation of
damaged organelles, protein aggregates, and invading pathogens
through a lysosome‐dependent pathway. The process plays a crucial
role in various biological functions in maintaining cellular home-
ostasis (Kim & Klionsky, 2000; Klionsky & Emr, 2000). Recently,
autophagy pathway takes participate in the pathogenesis of brain
injury after TBI (Feldmann et al., 2019). In a controlled cortical
impact (CCI) system model of TBI in vitro and in vivo, autophagy
markers such as microtubule‐associated protein light chain 3 (LC3)‐II
and beclin‐1 are significantly increased, sequestosome 1 (SQSTM1/
p62) are remarkably decreased, indicating that autophagic activity is
persistently activated after TBI (Au et al., 2017; Erlich, Shohami, &
Pinkas‐Kramarski, 2006; Liu, Chen, Dietrich, & Hu, 2008; Sadasivan,
Dunn, Hayes, & Wang, 2008; Sebastiani et al., 2017). Conversely,
autophagy inhibitors 3‐methyladenine (3‐MA) and chloroquine (CQ)
have precisely the opposite effect on TBI (Luo et al., 2011; Zeng et al.,
2018). Here, N‐methyl‐d‐aspartate receptor 2B (NR2B) and polox-
amer 188 (P188) stimulate autophagy following TBI both in vivo and
in vitro (Bao et al., 2016; Bigford, Alonso, Dietrich, & Keane, 2009).
The c‐Jun NH2‐terminal kinase (JNK) also provokes neuron
autophagy via p53 phosphorylation in response to TBI (Hong et al.,
2012). However, administration of bone marrow stromal cells
(BMSCs) diminishes autophagy after TBI (Sun et al., 2014). These
observations imply that the involvement of autophagy contributes to
the pathophysiological responses following TBI.
In this review, we mainly focus on the recent discoveries of the
beneficial and detrimental roles of autophagy concerning neurologi-
cal properties, which may be involved in the pathogenesis of TBI.
Furthermore, we summarize the correlation between oxidative
stress, inflammation, apoptosis, and autophagy after TBI. Finally,
compounds and drugs targeting the autophagy pathway are well
elaborated in the literature. Therefore, autophagy provides a
promising pharmacological intervention for the treatment of TBI
and its complicated management.
2 | T H E PR O P E R T I E S O F AU T O P H A G Y
AF TER TBI
2.1 | Beneficial role of autophagy
Accumulating evidence has demonstrated that autophagy, the chief
machinery pathway for bulk elimination of aberrant cell components,
is persistently increased after both experimental and clinical TBI
models (Zhang et al., 2008). Herein, connexins (CXs, also termed gap
junctions) are membrane proteins with dual‐channel functions that
permit the intercellular exchange of metabolites, ions, and small
molecules (Bennett, Contreras, Bukauskas, & Sáez, 2003). Astrocytic
p‐CX43 promotes autophagy in the hippocampal by the activation of
P2X7 receptor (P2X7R), contributing to TBI‐induced cognitive
deficits repair (Sun et al., 2014; Sun et al., 2015). In turn, autophagy
is an important regulator of p‐Cx43 and CX40 degradation in the
hippocampal following TBI (Chen et al., 2017; Sun et al., 2015).
ZENG ET AL.
Administration of docosahexaenoic acid (DHA) activates autop-
hagic flux, and subsequently improving cognitive function recovery
and reducing brain damage upon TBI (Yin et al., 2018). Short term
caloric restriction (CR) prevents cognitive impairment after mild TBI,
which is accompanied by increasing autophagy and suppressing
astrocyte activation (Liu, Wang et al., 2017). Posttreatment with
Morin improves memory impair via enhanced autophagy upon mild
TBI (El‐Gazar, Soubh, Mohamed, Awad, & El‐Abhar, 2019). NIX3, also
called BNIP3L (Bcl‐2/E1B‐19K‐interacting protein 3‐like), amelio-
rates brain water content and neurological deficits after TBI via the
induction of autophagy (Ma et al., 2019). Mesenchymal stem cells
overexpressing interleukin10 (MSCs‐IL‐10) transplantation induces
autophagy to protect against TBI‐induced neuronal damage (Maiti
et al., 2019). Taken together, the stimulation of autophagy pathway
confers pivotal neuroprotective effects following TBI.
2.2 | The detrimental effect of autophagy
On the contrary, various cellular factors and molecules regulate
autophagic activity that play a detrimental role in the progression of
TBI. The peptide apelin‐13, an endogenous ligand for the APJ
receptor, is abundantly observed in the nervous systems. For
instance, apelin‐13 significantly mitigates autophagy, and it may
contribute to ameliorate TBI‐induced brain damage (Bao et al., 2016;
Bao, Zhang, Han, & Dai, 2015). Interestingly, neurons transactivating
transduction protein with ubiquitin carboxy‐terminal hydrolase L1
(TAT‐UCH‐L1) and Wnt/β‐catenin reduce autophagy to protect brain
injury against CCI, a well documented TBI model (Liu et al., 2017;
Zhang et al., 2018). The specific necroptosis inhibitor necrostatin‐1
(NEC‐1) and p53 antagonist pifithrin‐α (PFT‐α) decrease autophagy
to attenuate brain damage suffering from TBI (Huang et al., 2018;
Wang et al., 2012).
Hydrogen sulfide (H2S), a novel gaseous neuromodulator, has
been reported to exert neuroprotectant following TBI. Indeed, NaHS
(a H2S donor) restrains brain edema and improves behavioral
symptoms in TBI via the suppression of autophagy (K. Xu et al.,
2018; Zhang et al., 2014). Administration of H2S‐synthesizing
enzyme 3‐mercaptopyruvate sulfurtransferase (3‐MST) reverses
these neuroprotective agents by enhancing autophagy after TBI
(Zhang et al., 2017). The zinc chelator N,N,N’,N’‐tetrakis‐(2‐pyridyl-
methyl) ethylenediamine (TPEN) and (Gly14)‐humanin inhibit autop-
hagy in injured hippocampal neurons, thus improving morphological
and functional outcomes after TBI (Wang et al., 2013; Zhao, Liu, Ma,
Zhang, & Liang, 2018). Vitamin D active metabolite calcitriol
attenuates neurological deficits in the brain cortex region following
TBI, which is highly associated with suppressing autophagy (Cui et al.,
2017). Furthermore, knockdown of forkhead box (foxO) 3a improves
neurological dysfunctions in the hippocampus, via the downregula-
tion of autophagic flux (Sun, Zhao et al., 2018).
MicroRNAs (miRNAs) dysfunction are aberrantly expressed in
the hippocampus after the experimental model of TBI. For
example, overexpression of miR‐23b prevents cognitive impair-
ments by directly inhibiting ATG12‐mediated autophagic activity
ZENG ET AL.
upon TBI (Sun, Liu et al., 2018). miR‐27a protects against TBI‐
induced brain damage though a mechanism suppressing FoxO3a‐
mediated autophagy (Sun et al., 2017). Notably, increased both
miR‐21‐5p and miR‐124‐3p in microglial exosomes attenuate
neuronal autophagy, thus abrogating TBI‐induced brain injury in
vitro and in vivo (Li, Huang, Yin et al., 2019; Li, Huang, Zhu et al.,
2019). Therefore, multiple miRNAs take participate in the
pathophysiological outcomes of TBI via the inhibition of autop-
hagy. Long noncoding RNA CRNDE (lncRNA CRNDE) silencing
reduces autophagic flux to promote the nerve repair following TBI
(Yi et al., 2019). Collectively, targeting autophagy by suppressors
serves as a valuable therapeutic strategy for TBI.
3 | DUAL ROLES O F M ITOP HAGY
F O L L O W I N G TB I
Mitophagy plays a prominent role in the selective degradation of
damaged mitochondria by autophagy, therefore maintaining mito-
chondrial quality control (Gustafsson & Dorn, 2019). Some studies
have demonstrated that dysfunction of mitophagy is closely
associated with the pathophysiology of TBI (Chen et al., 2016).
Recently, it has been observed that the reduction of mitochondrial
fission Drp1 with mitochondrial division inhibitor 1 (mdivi‐1)
prevents TBI‐triggered blood–brain barrier (BBB) and cell death in
vitro via blocking mitophagy (Wu et al., 2018). However, Niu, Dong,
Xu, Zhang, and Liu (2019) strongly argue that mdivi‐1 represses
mitophagy to aggravate neurological manifestations in a rat model of
mild TBI. Therefore, it is remain unclear that how mitophagy affects
the pathological process of TBI. Of note, melatonin (N‐acetyl‐5‐
methoxytryptamine) and cardiolipin (CL) decrease neuronal cell
death and alleviate behavioral deficits following TBI via enhancing
mitophagy, and these neuroprotecive effects abolish by inhibiting
mitophagy with 3‐MA (Chao et al., 2019; Lin et al., 2016). In vivo CCI‐
induced TBI model, mitophagy induced by extracellular signal‐
regulated kinase (ERK)/nuclear factor‐erythroid2‐like2 (Nrf2)/heme
oxygenase‐1 (HO‐1) diminishes intestinal mucosal damage and
epithelial barrier dysfunction, thus leading to TBI‐evoked gastro-
intestinal diseases (Liu, Bao et al., 2017). Taken together, mitophagy
plays a dual role in pathological condition of TBI and its complication.
4 | RELATIONSHIP BE TWEE N O XIDATIVE
S T R E S S , I N F L A M M A T IO N , AP O P T O S I S , A N D
AUTOPH AGY
4.1 | Oxidative stress regulates autophagy
Currently, oxidative stress and autophagy are believed to play an
essential role in brain injury after TBI. To determine the autophagic
activity whether it can be regulated in response to oxidative stress,
treatment of antioxidant c‐glutamylcysteinyl ethyl ester (GCEE)
partially blocks autophagy, thereby improving neurologic and
behavioral outcome following TBI (Clark et al., 2008; Lai et al.,
| 3
2008). Of note, tetrahydrocurcumin (THC) has shown to induce
antioxidant activity in vitro and in vivo. However, administration of
THC ameliorates cerebral edema, inhibits apoptosis, and improves
neurological deficits after TBI. The neuroprotection of THC occurs
via initiating autophagy (Gao et al., 2016, 2017). Consistently,
fucoxanthin with antioxidant properties confers neuroprotective
role in models of TBI, which is closely associated with enhancing
Nrf2‐autophagy in vitro and in vivo (Zhang et al., 2017). Altogether,
oxidative stress contributes to neuropathology following TBI by
influencing autophagy.
4.2 | Autophagy modulates inflammatory response
Several studies have demonstrated that interleukin‐33 (IL‐33)
improves neurological function and ameliorates cerebral edema in
model of TBI via partly reducing autophagy and neuroinflammation,
revealing that autophagy and inflammatory cascades are an essential
events in brain injury after TBI (Fairlie‐Clarke et al., 2018). However,
the correlation between autophagy and inflammation remains poorly
understood. Multiple inflammatory factors, such as stimulator of
interferon genes (STING; Nazmi et al., 2019), toll‐like receptor 4
(TLR4; Zhou, Andonegui, Wong, & Kubes, 2009), and so forth, are
known to be critical mediators of the inflammatory reaction in the
central nervous systems. Accordingly, STING mediates TBI‐induced
neuroinflammation, thus contributing to autophagy dysfunction
(Abdullah et al., 2018). Genetic ablation of TLR4 delays neuroin-
flammatory response and subsequently aggravates brain damage
after TBI by inhibiting autophagy (Jiang et al., 2018). Simultaneously,
TLR4 antagonist resatorvid (TAK‐242) diminishes neuronal autop-
hagy in the hippocampus upon TBI by MyD88/TRIF‐NF‐κB signaling
(Feng, Gao et al., 2017). In particularly, rosiglitazone (RSG) and
ketamine improve the behavioral and histopathological outcomes
after TBI, carrying out these anti‐inflammatory properties via the
downregulation of autophagy (Wang et al., 2017; Yao, Zheng, &
Zhang, 2015). However, the antiepileptic drug valproic acid (VPA)
inhibits TBI‐induced inflammatory response in vivo due to increased
Nrf2/ARE‐mediated autophagy (Chen, Wang et al., 2018). These
finding indicate that inhibition of inflammatory process acts as a
useful tool for TBI via the modulation of autophagy.
4.3 | The dual role of autophagy on apoptosis
It is widely known that various forms of cell death, especially in
apoptosis, occurring following TBI is modulated through autophagy
signaling pathway (Jin, Wang, Yang, Zhang, & Dai, 2017; Sarkar et al.,
2014). Here, moderate hypothermia reduces microglial activation by
promoting apoptosis and inhibiting autophagy, indicating the
connecting between autophagy and apoptosis in TBI (Zhang et al.,
2018). More importantly, moderate hypothermia significantly alle-
viates cell death both in ipsilateral hippocampus and in the injured
cortex after fluid‐percussion TBI through the activation of autophagy
(Jin et al., 2015a, 2015b). The suppression of autophagy with 3‐MA
deteriorates long‐term behavioral outcome upon post‐TBI moderate
 4
|

T A B L E 1 Roles of autophagy following TBI

Molecules TBI models Pathways Properties Ref.
NR2B Fluid‐percussion injury Promotes autophagy ? Chen et al. (2017)
P188 Weight‐drop, PC‐12 Promotes autophagy ? Chen et al. (2018)
JNK Marmarou’s weight‐drop Promotes autophagy ? Chen et al. (2018)
BMSCs Weight‐drop device Inhibits autophagy ? Chen et al. (2019)
CX43 Marmarou’s weight‐drop Promotes autophagy via P27R Improves cognitive deficits Cui et al. (2017); Cui et al. (2014)
Autophagy CCI, marmarou’s weight‐drop CX40 and CX43 degradation ? Cui et al. (2015); Ding et al. (2015)
DHA CCI Promotes autophagy flux Improves cognitive functions and reduces brain damage Du et al. (2016)
CR Marmarou’s weight‐drop Promotes autophagy Improves cognitive function Du et al. (2018)
Morin Marmarou’s weight‐drop Promotes autophagy Improves impair memory El‐Gazar et al. (2019)
NIX3/BNIP3L Weight‐drop device Promotes autophagy Ameliorates brain water content and neurological deficits Erlich et al. (2007)
MSCs‐IL‐10 CCI Promotes autophagy Protect against TBI‐induced neuronal damage Erlich et al. (2006)
Apelin‐13 Marmarou’s weight‐drop Inhibits autophagy Ameliorates brain edema and apoptosis Fairlie‐Clarke et al. (2018); Fang et al. (2019)
TAT‐UCH‐L1 CCI Inhibits autophagy Protect against brain injury Feldmann et al. (2019)
Wnt3a CCI Inhibits autophagy Improves functional recovery Feng et al. (2017)
NEC‐1 Weight‐drop model Inhibits autophagy Attenuates brain damage Feng et al. (2016)
PFT‐α CCI Inhibits autophagy Attenuates brain damage Feng et al. (2016)
H2S Marmarou’s weight‐drop Inhibits autophagy Mitigates brain edema and improves behavioral symptoms Feng et al. (2017); Gao et al. (2016)
3‐MST CCI Promotes autophagy ? Gao et al. (2017)
TPEN CCI Inhibits autophagy Improves morphological and functional outcomes Gustafsson and Dorn (2019)
[Gly14]‐humanin CCI Inhibits autophagy Improves morphological and functional outcomes He et al. (2018)
Calcitriol CCI Inhibits autophagic activity Attenuates neurological deficits Hensley et al. (2016)
FoxO3a Marmarou’s weight‐drop Promotes autophagy Aggravates neurobehavioral deficits Hong et al. (2012)
MiR‐23b Marmarou’s weight‐drop Inhibits autophagic activity Prevents cognitive impairments Huang et al. (2018)
MiR‐27a Marmarou’s weight‐drop Inhibits autophagy Ameliorates brain damage Jiang et al. (2018)
MiR‐21‐5p CCI Inhibits rab11a‐mediated autophagy Attenuates brain injury Jin et al. (2016)
MiR‐124‐3p Marmarou’s weight‐drop Inhibits autophagy via CX43 Protect against brain injury Jin et al. (2015a)
lncR‐CRNDE CCI Promotes autophagy Nerve damage Jin et al. (2015b)
(Continues)
ZENG
ET AL.
ZENG ET AL. | 5

Abbreviations: BBB, blood–brain barrier; BMSCs, bone marrow stromal cells; CX43, connexin43; CR, caloric restriction; DHA, docosahexaenoic acid; FoxO3, forkhead box 3; H2S, hydrogen sulfide; MSCs‐IL‐
10, mesenchymal stem cells overexpressing interleukin10; miR, microRNA; 3‐MST, 3‐mercaptopyruvate sulfurtransferase; Mdivi‐1, mitochondrial division inhibitor 1; NR2B, N‐methyl‐d‐aspartate receptor 2B;
hypothermia, as a result of increased apoptosis (Jin, Lei, Lin, Gao, &

NEC‐1, necrostatin‐1; NIX3/BNIP3L, Bcl‐2/E1B‐19K‐interacting protein 3‐like; P188,poloxamer 188; PFT‐α, pifithrin‐α; TAT, transactivating transduction protein; TBI, traumatic brain injury; TPEN,zinc
Jiang, 2016). Poly‐arginine R18 attenuates apoptosis and activates

Kim and Klionsky (2000); Klionsky and

neurocyte cell growth by promoting autophagy in TBI (Batulu et al.,
2019). Melatonin and omega‐3 polyunsaturated fatty acids (ω‐3
PUFA) promote autophagy to inhibit neuronal apoptotic pathway,
thus protecting brain damage after TBI (Chen, Pan et al., 2018; Ding
Langlois et al. (2006) et al., 2015). These findings suggesting the neuroprotective role of
autophagy in apoptosis after TBI.
Lai et al. (2008)

However, growing evidence has revealed that autophagic flux is

Emr (2000)

a detrimental effect of apoptosis after TBI. Here, FTY720 (also

termed as fingolimod) decreases TBI‐induced apoptosis though
Ref.

enhancement of autophagy (Zhang, Ding, Wang, Wu, & Xu, 2016).

The neurotrophic factor fibroblast growth factor‐2 (FGF2) attenu-
Ameliorates neuronal death and improves behavioral deficits

ates apoptosis, and thus improving functional recovery in the early

Attenuates BBB or aggravate neurological manifestations

stage of mild TBI through the inhibition of autophagy. Treatment

with autophagy agonist rapamycin abolishes these protective
effects of FGF2 (Tang et al., 2017). The selective p‐eIF2α
phosphatase inhibitor salubrinal improves TBI‐caused neurological
outcome, which is linked with the downregulation of apoptosis via
suppressing autophagy (Wang et al., 2019). Postconditioning of
sevoflurane delays neuronal apoptosis after TBI by activating PI3K/
AKT‐mediated autophagy (He et al., 2018). Recently, PLA2G4A‐
Ameliorates inflammation

mediated lysosomal membrane damage is involved in apoptosis by

autophagy inhibition following CCI‐induced TBI (Sarkar et al., 2019).
chelator N,N,N’,N’‐tetrakis‐ (2‐pyridylmethyl) ethylenediamine; UCH‐L1, ubiquitin carboxy‐terminal hydrolase L1.

Taken together, apoptosis induced by autophagy pathway con-

tributes to the pathogenesis of TBI.
Properties

5 | A U T O P HA G Y I N T B I‐I N D U C E D
Inhibits autophagy and mitophagy

COMPL I CATION S

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegen-

Promotes autophagy
Promotes autophagy

erative disease characterized by upper and lower motor neuron cell

death. It has been reported that TBI exacerbates ALS‐related
TDP43 mutation in cortical neurons following TBI, indicating TBI is
Pathways

considered as a predisposing factor for the pathology of ALS

(Wiesner et al., 2018). Interestingly, traumatic injury causes stress
granule formation, thus leading to motor dysfunctions in ALS
(Anderson et al., 2018). In G93A‐SOD1 transgenic mice ALS model,
the female sex hormone progesterone (PG) promotes autophagy
flux in the spinal cord to protect against motoneuronal death.
Moreover, autophagy inhibitor 3‐MA reverses these PG effects,
revealing that PG delays moto neuron degeneration in ALS
TBI models

progression via initiating autophagy in vitro and in vivo (Kim, Kim,

Cho, Kim, & Koh, 2013). In addition, TBI‐induced enhancement of
CCI

CCI
CCI

autophagy via ERK1/2/mTOR/Stat3 pathway mitigates apoptosis,

(Continued)

inflammation, and oxidative stress in lung tissues, improving

pulmonary barrier function, oxygenation function, and static
compliance in acute lung injury (ALI), whereas the interruption of
Cardiolipin
Molecules

Melatonin
TABLE 1

autophagy aggravates these protective effects (Xu et al., 2018),

Mdivi‐1

indicating that ERK1/2/mTOR/Stat3‐mediated autophagy may be

valuable in the treatment of TBI‐triggered ALI. Taken together,
 6
|

T A B L E 2 Summary about compounds and drugs targeting the autophagy pathway following TBI

Forms Compounds/drugs TBI models Mechanisms Functions Ref.

Diterpenoid lactone
Isaria sinclairii metabolite
Fatty acid metabolite
Flavonoids
Flavonoids
Flavonoids
Picrohiza kurroa extractive
Polyphenols
Oxidoreductase coenzyme
Sulfur amino acid metabolite
Flavonoids
Buffering agent
Anticancer
Antidote
Volatile anesthetics
Epilepsy
Macrolide antibiotics
β‐Lactam antibiotics
ANDRO Hypoxia‐injured Promotes autophagy Protects against hypoxia injury Wu et al. (2018)
astrocytes
FTY720 Weight‐drop Increases autophagy Reduces brain edema, improves Sun et al. (2014)
neurobehavioral function
ω‐3 PUFA Feeney Increases SIRT1‐mediated Attenuates neuronal apoptosis Sun et al. (2015)
deacetylation of autophagy
Luteolin Mamadou’s weight‐drop Enhances autophagy Reduces neuronal degeneration, alleviates Xu et al. (2014)
brain edema, and BBB disruption
Baicalin Weight‐drop Enhances autophagy Improves motor functions, reduces cerebral Xu et al. (2018)
edema, and BBB disruption
Quercetin Marmarou's weight‐drop Inhibits autophagy Attenuates neurological impairment and Xu et al. (2018)
improves cognitive function
Apocynin CCI Suppresses autophagy Ameliorates neurobehavioral deficits, brain Yao et al. (2015)
edema, and neuronal damage
RV Astrocyte and CCI Suppresses autophagy Improves cognitive function, neurological Ye et al. (2017); Yi et al. (2019);
impairment, and brain edema Yin et al. (2018); Zeng et al.
(2018)
PQQ Astrocyte and Feeney Inhibits autophagy Improves brain function and enhances cell Zhang et al. (2018); Zhang et al.
viability (2018)
LKE Central fluid‐percussion Reduces autophagy Improves long‐term behavioral outcome and Zhang et al. (2016)
neuropathology
Co‐ultraPEALut CCI Reduces autophagy Improve neurobehavioral functions and Zhang et al. (2017)
neuropathology
EPPS CCI Ameliorates autophagic flux Improves motor, cognitive functions, and Zhang et al. (2017)
reduces axonal injury
17‐AAG CCI Promotes autophagy Attenuates brain edema, decreases neuronal Zhang et al. (2014)
death, and improves motor function
MB CCI Promotes autophagy Attenuates brain edema, improves Zhang et al. (2017)
neurological deficit, and neuronal death
Sevoflurane Feeney Promotes PI3K/Akt‐mediated Attenuates neuronal apoptosis and alleviates Wang et al. (2017)
autophagy brain edema
VPA Feeney Promotes Nrf2/ARE‐mediated Promote functional recovery Ma et al. (2019)
autophagy
Rapamycin Weight‐drop Promotes autophagy and mitophagy Improves cognitive functions Zhang et al. (2008); Zhang et al.
via repressing NLRP3 inflammasome (2019); Zhao et al. (2018)
CTX Mamadou’s weight‐drop Suppresses autophagy Reduces brain edema and improves cognitive Zhao et al. (2016)
function deficits
ZENG

(Continues)
ET AL.
ZENG ET AL. | 7

nesulphonic acid; LKE, lanthionine ketimine ethyl ester; MB, methylene blue; PQQ, pyrroloquinoline quinone; RSG, rosiglitazone; RV, resveratrol; ω‐3 PUFA, omega‐3 polyunsaturated fatty acids; VPA, valproic
autophagy pathway may represent a novel therapeutic strategy for

Abbreviations: 17‐AAG, 17‐allylamino‐demethoxygeldanamycin; ANDRO, andrographolide; CCI, controlled cortical impact; CTX, ceftriaxone; CQ, chloroquine; EPPS, 4‐(2‐hydroxyethyl)‐1‐piperazinepropa-
the treatment of TBI‐induced complications.

Nazmi et al. (2019)

Zhou et al. (2009)

6 | CO MPOU NDS TA RGET THE

Lin et al. (2014)

AUTO PHA GY P ATH WAY A FTER TBI

To date, various compounds have been used to enhance or weaken

Ref.

autophagic activity following TBI. Accordingly, diterpenoid lactone

andrographolide (ANDRO) is isolated from Andrographis paniculata
that protects against hypoxia‐injured astrocytes by promoting
Attenuates brain edema and improves

autophagy (Du et al., 2018). The synthetic compound FTY720 is also

derived from metabolite modification of Isaria sinclairii. The neuro-
protective role of FTY720 is accompanied by the induction of
Promotes functional recovery
Alleviates functional deficit

autophagy (Zhang et al., 2016). Flavonoids such as baicalin, luteolin

(Lut), and quercetin are ubiquitously exist in various fruits and
neurological function

vegetable. Postinjury treatment with Lut and baicalin protect against

brain damage following TBI via enhanced autophagy (Fang et al.,
2019; Xu et al., 2014).
Functions

Nevertheless, the neuroprotection of quercetin in the hippo-

campus following TBI is closely associated with the suppression of
autophagy via activating PI3K/Akt pathway (Du et al., 2016).
Suppresses autophagy via PI3K/Akt/

Apocynin, a natural organic compound derived from the root

extract of Picrohiza kurroa, alleviates neurobehavioral deficits,
reduces cerebral edema, and BBB disruption by the inactivation
of autophagy pathway (Feng, Cui et al., 2017). The natural
Suppresses autophagy

Suppresses autophagy

polyphenolic compound resveratrol (3,5,4′‑trihydroxystilbene, RV)

mTOR pathway

improves cognitive function and neurological impairment as well as

Mechanisms

attenuates brain edema occurring TBI by suppressing autophagy

(Feng, Cui, Gao, Li, Jiang et al., 2016; Lin, Chen, Yang, & Shih, 2014).
Strikingly, RV reduces neuronal autophagy to exert neuroprotective
agent via the downregulation of TLR4/NF‐κB and the upregulation
of Sirt1 (Feng, Cui, Gao, Li, Li et al., 2016; Zhang, Li, Xu, & Li, 2019).
Modified weight drop

More importantly, pyrroloquinoline quinone (PQQ) is an anionic,

water‐soluble compound that provides neuroprotection following
TBI, this effect is linked to the suppression of autophagy (Ye, Zhang,
TBI models

Qian, Yin, & Yan, 2017; Zhang et al., 2017). Lanthionine ketimine
ethyl ester (LKE) and palmitoylethanolamide with luteolin (Co‐
CCI
CCI

ultraPEALut) compounds improve neurobehavioral functions and

Compounds/drugs

neuropathology in central fluid‐percussion injury after TBI accom-

panied by reducing autophagic flux (Cordaro et al., 2016; Hensley
et al., 2016). The buffering compound 4‐(2‐hydroxyethyl)‐1‐piper-
Ketamine

azinepropanesulphonic acid (EPPS) is significantly associated with

RSG
CQ

ameliorated autophagy, ultimately improving the cortex‐dependent

motor and hippocampal‐dependent cognitive deficits after TBI
(Anthony Jalin, Jin, Wang, & Li, 2019).
Multiple attractive potential drugs targeting autophagy pathway
(Continued)

after TBI have been well described in the documents. 17‐Allylamino‐

demethoxygeldanamycin (17‐AAG) has long been in the treatment of
PPAR‐γ agonist
Antimalarial

cancer in clinical trials. Intriguingly, the neuroprotective action of 17‐

Anesthetics
TABLE 2

AAG is closely linked with enhanced autophagy, as the consequence

Forms

of attenuating brain edema, decreasing neuronal death as well as

acid.

improving motor function following TBI (Ma et al., 2015). The

8 |
inhibitory effect of antidote methylene blue (MB) and volatile
anesthetics sevoflurane on brain edema exhibits closely related to
the activation of PI3K/AKT‐mediated autophagy upon TBI (He et al.,
2018; Zhao, Liang, Xu, Yan, & Zhang, 2016). The antiepileptic drug
VPA attenuates TBI‐induced brain injury due to increased Nrf2/ARE‐
mediated autophagy after TBI (Chen, Wang et al., 2018). Rapamycin
is a macrolide antibiotic first developed as an antifungal agent, dues
to its anti‐immunosuppressive properties. Currently, accumulating
evidence has indicated that rapamycin aggravates both autophagy
and mitophagy following TBI by repressing NOD‐like receptor
protein‐3 (NLRP3) inflammasome, leading to neuroprotection (Chen
et al., 2019; Erlich, Alexandrovich, Shohami, & Pinkas‐Kramarski,
2007; Wang et al., 2017). However, the β‐lactam antibiotics
ceftriaxone (CTX) and antimalarial drug chloroquine (CQ) curb TBI‐
induced brain edema and improve cognitive function deficits by the
ZENG ET AL.
F I G U R E 1 The role of autophagy in TBI
autophagy plays an essential role in
pathophysiological processes, such as
oxidative stress, inflammatory response,
and apoptosis, thus contributing to
neurological properties of TBI. The
development of neurological functions
includes neuronal cell death, brain edema
and learning and memory impairments,
brain damage, and motor behavioral
function. Therefore, autophagy pathway
represents a potential clinical therapeutic
value for treatment of TBI. TBI, traumatic
brain injury [Color figure can be viewed at
wileyonlinelibrary.com]
suppression of autophagy occurring TBI (Cui et al., 2014; Cui et al.,
2015). In a rat model of TBI, ketamine is able to alleviate functional
deficits though the reduction of autophagy (Wang et al., 2017).
Consistently, RSG treatment reduces neuronal autophagy to promote
functional recovery after TBI (Yao et al., 2015). These findings
suggest that targeting autophagy pathway might provide a novel
clinical efficacy on TBI.
7 | CO NCL UDING REMA RKS AND FUT URE
DI R ECT ION S
In summary, we mainly focus on the key contribution of autophagy and
its properties in the pathogenesis of TBI. Accumulating evidence has
revealed that autophagy, a very well‐characterized cellular degradation
ZENG ET AL.
or recycling process, has been implicated in human and animal models
of TBI. Multiple cellular factors and molecules are considered to confer
beneficial and detrimental effect concerning autophagy, thus contribut-
ing to neurological functions of TBI (Table 1). Moreover, the correlation
between inflammation, oxidative stress, apoptosis, and autophagy are
completely described in TBI in vitro and in vivo. Intriguingly, various
compounds and multiple drugs target autophagic activity, as a
consequence of TBI progression (Table 2). Taken together, these
findings support the viewpoint that autophagy pathway is of great
importance in TBI and the modulation of this pathway provides
pharmacological approach for TBI and its complications (Figure 1).
From this point of view, knowledge gaps remains to be elucidated
detail mechanisms that cellular factors and contents determine
promoting or inhibiting autophagy pathway, ultimately contribute to
the progression of TBI. Among these, the connection between
oxidative stress, inflammation, apoptosis, and autophagy following
TBI need to be further investigated. It is worthy of comprehensive
understanding of the potential role of mitophagy, to lead to the
manifestation of TBI. Much of existing literature about compounds
and drugs directly and indirectly affecting autophagy pathway on
accounts of cell experiments in vitro and CCI‐triggered TBI in vivo. In
further, researchers should pay close attention in various animals and
even human experiment in clinical in vivo. The effects of agonists and
antagonists modulate the autophagy pathway upon TBI remain
elusive and need to be further explored. The optimization of
pharmacological inhibitors or the development of specific drugs to
help design of agent with more specificity and less side effects than
those currently in clinical. Therefore, targeting autophagy could be a
potential approach for TBI and its complications.
A C K N O W L E D GM E N T
This study was supported by the National Natural Science Founda-
tion of China (81803535), the National Natural Science Foundation
of Hunan (2018JJ6070), the Technology and Innovation Guiding
Program of Hunan (2017SK50207), and the Heath and Family
Planning Commission Science Foundation Projects of Hunan Pro-
vince of China (C20190121).
CO NFLICT OF I NTERE STS
The authors declare that there are no conflict of interests.
A UT HO R C ONT RI BU TIO NS
L. H. and H. Q. conceived the manuscript. Z. Z. and Y. Z. consulted the
literature. Z. Z. and Y. Z. taken participate in writing the initial draft
of the manuscript. L. H. and H. Q. revised the whole manuscript. All
authors reviewed the manuscript.
D A T A A V A I L A B I LI TY S TA T E ME N T
Research data not shared.
| 9
ORCI D
Zhiqing Zeng http://orcid.org/0000-0002-5374-608X
Lu He http://orcid.org/0000-0002-7367-2452
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How to cite this article: Zeng Z, Zhang Y, Jiang W, He L, Qu
H. Modulation of autophagy in traumatic brain injury. J Cell
Physiol. 2019;1–13. https://doi.org/10.1002/jcp.29173