brain

sciences
Review
The Current Role of Dexmedetomidine as Neuroprotective
Agent: An Updated Review
Zaara Liaquat 1 , Xiaoying Xu 2 , Prince Last Mudenda Zilundu 2 , Rao Fu 1, * and Lihua Zhou 1

1 Department of Anatomy, School of Medicine, Sun Yat-sen University, Shenzhen 518100, China;
[email protected] (Z.L.); [email protected] (L.Z.)
2 Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China;
[email protected] (X.X.); [email protected] (P.L.M.Z.)
* Correspondence: [email protected]; Tel.: +86-20-87332338

Abstract: Dexmedetomidine, selective α2-adrenergic agonist dexmedetomidine, has been widely

used clinically for sedation and anesthesia. The role of dexmedetomidine has been an interesting
topic of neonatological and anesthetic research since a series of advantages of dexmedetomidine,
such as enhancing recovery from surgery, reducing opioid prescription, decreasing sympathetic
tone, inhibiting inflammatory reactions, and protecting organs, were reported. Particularly, an
increasing number of animal studies have demonstrated that dexmedetomidine ameliorates the
neurological outcomes associated with various brain and spinal cord injuries. In addition, a growing
number of clinical trials have reported the efficacy of dexmedetomidine for decreasing the rates
of postoperative neurological dysfunction, such as delirium and stroke, which strongly highlights





 the possibility of dexmedetomidine functioning as a neuroprotective agent for future clinical use.
Mechanism studies have linked dexmedetomidine’s neuroprotective properties with its modulation of
Citation: Liaquat, Z.; Xu, X.;
Zilundu, P.L.M.; Fu, R.; Zhou, L. The
neuroinflammation, apoptosis, oxidative stress, and synaptic plasticity via the α2-adrenergic receptor,
Current Role of Dexmedetomidine as dependently or independently. By reviewing recent advances and preclinical and clinical evidence
Neuroprotective Agent: An Updated on the neuroprotective effects of dexmedetomidine, we hope to provide a complete understanding
Review. Brain Sci. 2021, 11, 846. of the above mechanism and provide insights into the potential efficacy of this agent in clinical use
https://doi.org/10.3390/ for patients.
brainsci11070846
Keywords: apoptosis; caspase 8; dexmedetomidine; excitatory amino acid transporter 3; excitotoxic
Academic Editors: María neurotransmitter; focal adhesion kinase; necrosis; nerve injury; neuroprotection; neuroinflammation
García-Fernández and Elisa
Martín-Montañez

Received: 24 May 2021

1. Introduction
Accepted: 23 June 2021
Published: 25 June 2021
Car accidents and falls are the main causes of nerve and brain injuries that can lead to
permanent damage and dysfunction of a limb [1]. Furthermore, there are greater chances
Publisher’s Note: MDPI stays neutral
that this injury may develop anxiety in later stages [2]. Consequently, various kinds of the
with regard to jurisdictional claims in
neuroprotective agent are tested preclinically and clinically on different steps of cascade in
published maps and institutional affil- neuronal damage to ameliorate the aforementioned issues, thereby restoring their function
iations. by preventing further damage [3]. One of the most pertinent neuroprotective drugs is
Dexmedetomidine (DEXM) which was approved in 1999 by the FDA as a short term (<24 h)
sedative agent [4,5]. In 2008, the USA granted another indication of DEXM for use as a
sedative agent in non-tracheal intubated patients before or during surgery [6–8].
Copyright: © 2021 by the authors.
Accordingly, the European Union approved DEXM in 2011 as an adult sedative agent
Licensee MDPI, Basel, Switzerland.
for ICU [9]. A selective α2 agonist, DEXM has broad-spectrum effects, including being
This article is an open access article
analgesic, sedative, and anxiolytic, with minimal depression of pulmonary function [9].
distributed under the terms and Previous works illustrated that DEXM has proved a crucial tool for critical patients by
conditions of the Creative Commons minimizing ventilation free hours [8,10]. On the other hand, it also attenuates delirium,
Attribution (CC BY) license (https:// improves postoperative cognitive dysfunction, and acts as a sympatholytic agent [11–13].
creativecommons.org/licenses/by/ Recently, it caught the attention of researchers and clinicians due to its cardioprotective [14],
4.0/). renoprotective [15], pulmonoprotective [16], and neuroprotective effects [17]. However,

Brain Sci. 2021, 11, 846. https://doi.org/10.3390/brainsci11070846 https://www.mdpi.com/journal/brainsci

Brain Sci. 2021, 11, 846 2 of 15

there has been very limited research regarding DEXM as a neuroprotective agent against
neuronal injury and only a few review articles have been reported. To the authors’ best
knowledge, there is not a single review article on the neuroprotective effect of DEXM
against neuronal injury. Therefore, to bridge this literature gap, an attempt has been made
to provide the latest updates on the most recent contributions about DEXM, and which
demonstrate the various growing research directions on its neuroprotective effects. The
main contributions of this work are:
1. It reviews recent studies in various animal models depicting DEXM’s anti-inflamma-
tory role.
2. Moreover, it elaborates the longitudinal studies of pre-and post-clinical trials on
DEXM, which prove its ability to modulate apoptotic and necrotic events and also
illustrate DEXM’s role in astroglia.
3. Finally, the proposed study describes all the viable neuroprotective mechanisms of
DEXM against nerve injury, which can support scientists and doctors in future studies.
The purpose of this article is to summarize and critically review the published data on
the neuroprotective mechanisms of DEXM. This article also addresses the recent clinical
applications of DEXM to have surfaced.
The rest of the paper is organized as follows. Section 2 illustrates DEXM’s phar-
macology, while Section 3 presents DEXM’s neuroprotective mechanisms, and Section 4
concludes the study.

2. Pharmacology of Dexmedetomidine
2.1. Pharmacokinetics of Dexmedetomidine
DEXM is FDA approved IV drug that extensively undergoes a first-pass effect with
a bioavailability of 16% [18]. It shows a better intranasal sedative and anxiolytic effect in
comparison to clonidine [19]. DEXM exclusively binds with plasma protein (albumin) has
the ability to cross the placenta and Blood-Brain Barriers (BBB) but its teratogenicity effect
has not yet been fully explored [20].
DEXM is mainly metabolized in the liver via N-glucuronidation through uridine 50 -
diphospho-glucuronosyltransferase (UGT2B10, UGT1A4) and cytochrome P450 (CYP2A6).
The average half-life of DEXM in a healthy individual is 2.1–3.1 h, while in ICU it is 2.2–3.7 h.

2.2. Pharmacodynamics of Dexmedetomidine

The pharmacodynamic effect of DEXM is mainly dose-dependent. The biphasic
hemodynamic responses, such as hypotension or hypertension, produce low or high
plasma concentrations, respectively [21].
The concentration-dependent hypnotic and sedative action of DEXM is mediated
through the activation of the α2 adrenergic receptor, which is anatomically located in the lo-
cus coeruleus [22]. The peculiar and unique pharmacodynamic properties of DEXM ensure
“cooperative sedation”, in which even patients in the asleep stage can be easily aroused [23].
DEXM also can reduce pain via the α2 adrenergic receptor that alters perception, weakens
the anxiolytic effect, and decreases the post-operative opioid need [24].

2.3. Adverse Effects of DEXM

DEXM’s main adverse effect is its hemodynamic instability because of α2 adrenore-
ceptor receptor activation that causes hypertension due to vasoconstriction, which leads
to reflex bradycardia via carotid or aortic baroreceptor mediated autonomic activation.
Moreover, DEXM is dose-dependent: a high dose of 1 or 2 µg/kg of DEXM over 2 min
is required for rapid sedation. However, at the aforementioned dose concentration, an
irregular and obstructive pattern of respiration has been reported [20].
The incidence of ventricular tachyarrhythmia, including ventricular fibrillation and
ventricular tachycardia, is reduced after DEXM infusion during surgery. Conversely,
DEXM shows no effects on atrial fibrillation [25], but overdose may cause I or II-degree
atrioventricular blockage [20].
Brain Sci. 2021, 11, 846 3 of 15

Newborn piglets experienced hypoxia and therapeutic hypothermia at a loading dose

of 1 µg/kg with a maintenance infusion of 1.0 to 0.6 µg/kg/h, due to underdevelopment
of the neonate cytochrome P450 enzyme and glucuronidation system. A few of the more
adverse effects of DEXM include nausea, vomiting, and xerostomia [26].

2.4. Dexmedetomidine a Selective Alpha 2-Adrenoceptor Agonist

In 1948, Ahlquist challenged the opinion that adrenergic receptors were excitatory or
inhibitory by differentiating the adrenergic receptors into an alpha and beta subtype [27].
The first α2-adrenoceptor agonist was manufactured in the early 1960s as a nasal decon-
gestant (clonidine) [28]. Paton and his co-workers in 1996 found that a subclass of alpha
adrenoceptors, located presynaptically, regulate the release of neurotransmitters [29]. This
led to the subdivision of alpha adrenoceptors into postsynaptic alpha-1 and presynaptic
alpha-2 adrenoreceptors. Other members of the α2 agonist receptors with α2/α1 selectivity
include DEXM (1620:1), xylazine (160:1), Detomidine (260:1), Medotomidine (1620:1), cloni-
dine (220:1), and Romifidine (affinity has not been confirmed yet) [30]. Alpha 2 adrenergic
receptor is a transmembrane receptor that was differentiated into three iso-receptors, α2a,
α2b, and α2c by Bylund. In contrast, its fourth type is only found in humans and is known
as the α2d receptor, which is shown in Table 1. α2 receptor mediates effects through
the potentiation of guanine-nucleotide regulatory binding proteins (G inhibitory protein),
which ultimately attenuate the cAMP level. α2-adrenoceptor is widely distributed in the
body, including the kidneys, pancreas, blood vessels, platelets, and eyes. Nonetheless,
DEXM exerts its effects on α2-adrenoceptor distributed areas [23]. All subtypes of α-2
adrenoceptor perform different functions that include sedation, hypnosis, analgesia, sym-
patholysis, and neuroprotection via α-2A subtype [31,32]. Contrarily, the α-2B subtype
is responsible for the suppression of central shivering, which causes peripheral vasocon-
striction and analgesic effects on different sides of the spinal cord [33]. On the other hand,
the stimulant induces locomotor activity, adrenaline outflow from the adrenal medulla,
and mediation of cognitive sensory processing and emotional behavior, such as mood
being controlled by α-2C [32]. In addition, DEXM performs all functions by binding with
α-2 adrenoceptor [34,35], which links with the heterotrimeric transmembrane Gi protein
that inhibits adenylyl cyclase. Inhibition of adenylyl cyclase decreases the formation of
30 50 cyclic adenosine monophosphate (cAMP), which acts as a second messenger. Gi protein
activation opens inward potassium K+ rectifying channels that result in neuronal cell
membrane hyperpolarization, which ultimately decreases the excitability of neuronal cells.
On the other hand, the α-2 receptor also functions on the Go protein that inhibits Ca2+
entry into the cell and inhibits phospholipase C activity. On the other hand, phospholi-
pase C inhibition attenuates Protein Kinase C (PKC), which has many roles in oxidative
stress and apoptosis. Additional randomized clinical data also reported the binding of
α-2 adrenoceptor with another undetermined G protein that works on sodium hydrogen
(Na+ /H+ ) exchanger [34,35], which is summarized in Figure 1.

Table 1. Alpha 2 receptor subtypes, anatomical location, and functions.

Alpha 2 Receptor
Anatomical Location Functions References
Subtype
Regulates the phase of awareness
CNS including the brain, spinal cord, produces anesthetic, sympatholytic
α2a [36–38]
and locus coeruleus responses, helps in arousal, and
vigilance
Liver, spleen, heart, Thalamus, smooth
α2b Vasoconstrictive. [39,40]
muscle cells of the blood vessel.
Hippocampus, locus coeruleus, Control anxiolytic and analgesic effects,
α2c [38–40]
especially in basal ganglia, platelets. hypnotic-sedative actions
Brain Sci. 2021, 11, 846 4 of 15

Figure 1. The possible DEXM neuroprotective mechanism is mediated by α2 adrenoreceptor, which links with heterotrimeric
transmembrane G inhibitory protein (Gi), which inactivates Adenyl cyclase (AC). Inactivation of AC attenuates the cAMP
level (act as the second messenger). Gi opens inward, rectifying the K+ channel and leading to neuronal membrane
hyperpolarization. Normally phosphoinositide (PI)hydrolysis to produce hydrolysis produces inositol 1,4,5-trisphosphate
(IP3) and diacylglycerol (DAG) and activates PKC, and has a role in oxidative stress and apoptosis. Agonist agent of α2
receptor (DEXM) via G0 blocks Ca2+ translocation and inhibits phospholipase C activity, reducing PKC activity. “↑” increase
and “↓” decrease.

2.5. Dexmedetomidine and Imidazoline Receptor

In 1987, Ernsberger et al. were the first to discover imidazoline binding sites in the
ventrolateral medulla [41], belonging to a non-adrenergic family identified by compounds
with an imidazoline moiety [42]. There are three imidazoline receptor subtypes found (I1,
I2, and I3), among them, I2 is found in the medulla and brain, mainly the frontal cortex [36].
The neuroprotective effect of DEXM is mainly modulated by I2 noradrenergic receptors, not
by I1 or I3 noradrenergic receptors [42]. I2 receptors associate with several distinct proteins
but the identities of these proteins remain elusive. Its heterogeneous structure includes I2A
and I2B subtypes, a division based on binding ability to the amiloride drug. Some data
reported the evidence of DEXM binding with I2, causing Ca2+ influx into chromaffin cells
and protecting neurons from damage. Nonetheless, DEXM’s neuroprotective effect via I2
Brain Sci. 2021, 11, 846 5 of 15

requires further investigation, as few of its molecular mechanisms do not provide implicit
information [43].
Manami Ingaki et al. [44] reported that Thapsigargin (non-competitive inhibitor of
the Sarco/endoplasmic reticulum Ca2+ ATPase) can induce apoptosis and increase the
influx of Ca2+ . DEXM suppresses the Ca2+ level via the I2 receptor present on the outer
membrane of mitochondria. The long-term potential (LTP) (a process of signal transmission
in excitatory neurons of the hippocampus) is believed to be involved in the construction of
neuronal circuits during learning and memory. DEXM can reduce LTP [45], and Yohimbine
(α2 adrenoreceptor antagonist) is unable to fully abolish the DEXM effect on LTP, but
combining with BU 224 hydrochloride (an imidazoline type 2 receptor antagonist) can
reverse its effect. This information proves that DEXM also can bind with the imidazoline
type 2 (I2) receptor [43,45].

3. Evidence of Dexmedetomidine as a Neuroprotective Agent

The role of DEXM as a neuroprotectant agent has been confined to animal experimen-
tal models. Even in laboratory animal models, the underlined neuroprotective mechanisms
are not explicitly understood. Various DEXM neuroprotective properties are briefly dis-
cussed below.

3.1. Role of Dexmedetomidine in Overview Pathogenesis of Neuronal Damage and Death

Neural damage pathogenesis is a complex process, as it involves multiple molecular
pathways. Numerous neuroprotective agents are applied to different types of neuronal
injury such as necrosis, apoptosis, oxidative stress, and so on. DEXM exhibits a neuropro-
tective ability by modulating inflammatory markers and molecular pathways, which are
summarized below [43].

3.2. The Influence of Dexmedetomidine against Necrosis

Necrosis is a type of irreversible cell death that usually occurs in acute phase injury.
The pathophysiology of irreversible cell death consists of many components including
the pre-necrotic event (pyroptosis) and the release of inflammatory markers, excitotoxic
neurotransmitters, reactive oxygen species, and so on. All these components play a vital
role in the pathogenies of cell death [46]. The signal transmission begins with a wave of
depolarization and then repolarization that causes action potential (AP). The AP process
exchanges cations of sodium (Na+ ) with potassium (K+ ), and during this process, the
neurotransmitter acts as a chemical messenger. It is released from pre-synapses and binds
to the corresponding receptor on a postsynaptic membrane, which causes depolarization or
hyperpolarization [47,48]. Neurotransmitters are released in response to many processes,
such as signal transmission, the release of hormones and peptides, and cell injury. Previous
data have demonstrated that excitatory neurotransmitters such as glutamate and aspartate
are released from the nerve terminal in response to nerve damage. These excitatory
neurotransmitters also precipitate further nerve damage [49,50]. Additionally, this causes
dysfunction of Na+ /K+ ATPase, which leads to membrane hyperpolarization. Imbalance
in levels of neurotransmitters such as catecholamine (CAT) increases nerve sensitivity to
glutamate. The glutamate release by chelation of extracellular Ca2+ ions is associated with
vesicular transportation. Glutamate binds to the NMDA (N-methyl-D-aspartate) receptor,
which is a subtype of the glutamatergic receptor [49]. Furthermore, it activates the nitric
oxide signaling pathway and enhances the intracellular Ca2+ ions that subsequently activate
intracellular catabolic and proteolytic enzymes, for instance, protease and lipase [51,52].
These enzymes generate oxygen-free radicals that damage the membrane and results
in cell death. Glutamate secretion is also regulated by mitogen-activated/extracellular
signal-regulated kinase (MEK) [53].
Experimental models corroborate DEXM’s ability to modulate glutamate, and its in-
hibitory effect releases glutamate by reducing the release of CAT. DEXM inhibits glutamate
release by binding with the α2 receptors that are expressed on neurons. This reduces
Brain Sci. 2021, 11, 846 6 of 15

the CAT release along with the CAT-associated nerve sensitivity for glutamate [53,54].
Additionally, DEXM directly blocks the MEK pathway and voltage-dependent calcium
channel. It improves the expression of excitatory amino acid transporter 1 by increasing
the N-methyl-D-aspartate receptor (NMDA) that decreases glutamate [55,56]. Excitatory
Amino Acid Transporter 3 (EAAT3) is a member of the glutamate transporter family that
removes glutamate from the synaptic cleft and extrasynaptic sites via glutamate re-uptake
into glial cells and neurons. DEXM enhances EAAT3 expression [54,55]. The aforemen-
tioned discussion concludes that DEXM could prevent neuronal damage by inhibiting
neurotransmitter release, as depicted in Figure 2.

Figure 2. Nerve injury causes dysfunction of NA/K ATPase, leading to an imbalance between neurotransmitters. Increasing
CAT level enhances the sensitivity of nerves to glutamate (Glu). Excessive Glu increases intracellular Ca2+ , which in return
activates the aforementioned pathways, resulting in cell death. Activation of the mitogen-activated/extracellular signal-
regulated kinase (MAK) pathway also increases Glu concentration. The α2 adrenoreceptor exerts its possible neuroprotective
mechanism by hyperpolarization, which blocks the Ca2+ entry into presynase. Low Ca2+ diminishes neurotransmitter
release (CAT) and Glu and also decreases nerve sensitivity for Glu. DEXM also enhances Excitatory amino acid transporter 3
(EAAT3) activity, which removes Glu from the synaptic cleft. Hyperpolarization also reduces NMDA receptors, which also
decreases firing and reduces intracellular Ca2+ . DEXM also blocks MEK, resulting in decreased excitotoxic neuronal injury.
Brain Sci. 2021, 11, 846 7 of 15

Pyroptosis is a proinflammatory form of cell death that regulates necrosis. The clin-
ical features of pyroptosis include rapid cell membrane rapture, cellular swelling, DNA
fragmentation, and extravagation of cellular components resulting in the death of a neigh-
boring healthy or normal cell, and inducing necrosis. The inflammasome is a protein
that works as a sensor to detect cellular damage and invading pathogens. The LPS is re-
leased in response to pyroptosis. The LPS upregulates leucine rich repeated kinase (LRRK),
nucleotide-binding domain (NLRP3), and apoptosis-associated speck like protein, Gasder-
min D expression. The assembly of NLRP3 leads to the release of caspase 1 depending on
cytokines IL-1β, IL-18 as well as Gasdermin D which mediate pyroptosis [57,58]. Previous
data reports that cells treated with DEXM were found to protect against LPS inducing
pyroptosis. Histone is a nuclear protein released from a dying cell into the extracellular
space. LPS challenge the cell increase concentration of histone; it has been found that
DEXM markedly inhibits histone release after LPS challenge [53,58,59].

3.3. The Response of Dexmedetomidine against Apoptosis

Apoptosis (programmed cell death) usually occurs in a late phase of injury and has
an integral role in the normal development of a tissue or organ. The process of apoptosis
involves B cell lymphoma/leukemia-2 (Bcl-2), a family of pro and anti-apoptotic regulatory
proteins. The process of cellular death is delicately balanced by these proteins, which assess
the integrity of the mitochondrial membrane, the release of cytochrome c, and potentiators
of other apoptotic factors. BCL Associated Death protein (BAD) is a pro-apoptotic protein
that is provoked by protooncogene protein C-akt (AKT) through phosphorylation of its
serine residue. After AKT activation, BAD attaches to a cytosolic protein called 14-3-3 to
reduce BCL-XL (anti-apoptotic protein), which delicately inhibits programmed cell death
by binding with Bax (pro-apoptotic protein) [59].
It can be inferred that BCL-2 and BCL-XL proteins perform their anti-apoptotic effects
by preventing the release of cytochrome C from mitochondria. Moreover, this also prevents
Bax translocation and maintains mitochondrial membrane potential. DEXM potentially
exhibits an anti-apoptotic property by regulating many pro and anti-apoptotic proteins,
as it increases BCL2 [59], pERK concentration, and Murine Double Minute 2 (MDM-
2). An increase in MDM-2 results in a reduction of pro-apoptotic mediator p53 [60].
Subsequently, it also increases Focal Adhesion Kinase (FAK), as well as the concentration
of phosphorylated extracellular signal regulator kinase 1/2 (ERK1/2) [61]. FAK regulates
its anti-apoptotic property by activating Phospohoinositide 30 -OH Kinase (PI3K) and the
AKT pathway [62]. FAK simultaneously activates Nuclear Factor-kB (NF-kB), Inhibitor
of Apoptosis Proteins (IAP), and IAP subtypes such as cIAP-1, cIAp-2, and XIAP, which
alleviates apoptosis by inhibiting the caspase 3 activation [43].
The global cerebral ischemic insult may activate adaptive pathways and alter gene
expression within the area of injury. Hypoxia Inducible Factor (HIF-1α) is expressed
in response to hypoxia and it exponentially escalates several other genes, such as Vas-
cular Endothelial Growth Factor (VEGF), erythropoietin, and DNA damage response 1
(REDD1/RTP801). The role of REDD1 is controversial in injury, but the reported data
give evidence that it suppresses lactate dehydrogenase LHD release from neurons [58].
Data also indicate that DEXM upregulates HIF-1α, VEGF [63], and REDD1 [62] expres-
sion to protect the cell from oxygen-glucose deprivation induced injury. Oxygen glucose
deprivation (OGD) insult is commonly used in vitro for hypoxia/ischemic modeling [64].
OGD exposure to cells causes deterioration of mitochondrial function and cell viability
loss, and this death is usually by apoptosis (55%) and not by necrosis (only 7%) [63]. Fur-
thermore, 1 µM of DEXM through the I2 imidazole receptor reduces the OGD induced
cell death apoptosis to 22% and necrosis to 2% [62]. Moreover, a cell pretreated with BU
224 or idazoxan (I2 imidazoline antagonist) inhibits the DEXM protection by 82.3% and
92.4%, respectively. DEXM binds the I2 imidazole receptor, which activates the PI3K/AKT
pathway and increases the HIF1α, VEGF, and REDD1 gene expression [62]. The imbalance
between two pathways (phosphoinositide 30 -OH kinase (PI3K) and AKT protein kinase)
Brain Sci. 2021, 11, 846 8 of 15

plays a significant role in apoptosis [62], as these signaling pathways (PI3K/AKT) act
with anti-apoptosis to enhance cell survival and proliferation [65]. DEXM phosphorylates
AKT and increases expression of PI3K [65,66]. Furthermore, DEXM counteracts the OGD
influenced inhibition of the p38 Mitogen Activated Protein Kinase (MAPK)/ERK1/2 path-
way by elevating the phosphorylated level of p38 MAPK and ERK1/2 [67]. Caspase-3
expression was further investigated to observe the DEXM anti-apoptosis effect that protects
against OGD-induced injury. Caspase-3 activation was increased by 8.7-fold due to OGD
insult, while DEXM mitigated OGD induce caspase-3 expression to 1.8-fold [62]. The role
of DEXM in apoptotic events is demonstrated in Figure 3.

Figure 3. (1) Activation of death receptor release Caspase 8 that helps Ba bind with BCL-XL and releases cytochrome C (Cyt
C) from mitochondria. Cyt C activates caspase cascade induced apoptosis. (2) Stress activates FAK, which activates AKT/PI3
K and ERK 12 . AKT helps BAD serine residue phosphorylation. Phosphorylated BAD attaches cytosolic 14-3-3 protein that
unbinds Ba with BCL-XL, attenuating apoptosis. (3) OGD induces necrosis by decreasing the p38 Mitogen-activated protein
kinase (MAPK)/ERK1/2 pathways that attenuate apoptosis. (4) MDM2 reduces p53 activity, which induces apoptosis.
DEXM enhances FAK activity and also phosphorylates AKT and increases expression of PI3K, increasing detachment
of Ba-BCL-XL. DEXM counteracts OGD-influenced inhibition by elevating the phosphorylated level of p38 MAPK and
ERK1/2. DEXM modulates p53 activity via Mdm2.
Brain Sci. 2021, 11, 846 9 of 15

3.4. The Response of Dexmedetomidine against Immunologic Response

The significance of immunological or inflammatory response is not entirely clear be-
cause, on the one hand, it exacerbates oxidative stress, and on the other hand its phagocytes
kill or damage nerve cells and help maintain neurogenesis. Inflammation or neuroinflam-
mation is a complex process that involves many molecules, including pro-inflammatory cy-
tokines (interleukins, TNF), chemokine, and inflammatory cells (monocytes, macrophages,
Natural Killer Cell (NKC), astrocytes, and lymphocytes). Interleukin 1β or simple IL-1β
has many names, such as a leukocytic endogenous mediator, mononuclear cell factor, leuko-
cytic pyrogen, lymphocyte activating factor, and so on. It is a pro-inflammatory cytokine
that is secreted by phagocytes (macrophage and monocytes). During acute insult, IL-1β is
first released by microglia and then by astrocytes. Moreover, IL-1β has the ability to induce
the release of other cytokines such as Tumor Necrotic Factor- α (TNF-α) and IL-6, which
are released from astrocytes and microglial cells. IL-6 acts as a pro and anti-inflammatory
cytokine, which affects metabolism, organ development, and hematopoiesis. In addition,
IL-6 plays an essential role in infection, inflammation, neurodegenerative disease, and
other ischemic injuries.
IL-1β induces mRNA expression of IL-6 in glioma cells through many pathways
like phosphorylation of p38 Mitogen-Activated Protein Kinases (MAPK), Stress Activated
Protein Kinase (SAPK)/c-Jun-N Terminal Kinase (JNK), and nuclear factor kappa-B kinase
IκB/NF-κB [68,69]. IL-1β activities and synthesis IL-6 by binding within SMase/Src
kinase/NMDA receptor through Calmodulin-Dependent Protein Kinase II and cAMP
Response Element-Binding Protein (CamKII/CREB) activation pathway. DEXM exerts
neuroprotective effects directly and indirectly by astrocytes as well as reduces the number of
activated macrophages that involves in inflammation. Cell pretreated with DEXM decreases
GFAP level (marker for astrocytes) [70] and CD116B level (marker for macrophage and
monocytes) [70,71]. Previous work reported that DEXM alleviates IL-1 β-inducing-IL-6
release but it exerts very little effect on IL-6 suppression [72,73].
It has been experimentally proven in [72] that DEXM decreases IL-6 through suppres-
sion of IL-β but independently of the adenylyl cyclase-cAMP pathway, as 8-Bromo cAMP
(analog of cAMP) increases the IL-6 level and Forskolin (direct activator of adenylyl cyclase)
significantly magnifies the IL-1β-induced-release of IL-6. However, DEXM is unable to
affect the forskolin-induced cAMP accumulation [72]. Yohimbine (α2-adrenoceptor antago-
nist) did not invert the suppressive effects of DEXM on the IL-1β-induced IL-6 release. It
seems that DEXM, by employing α2-adrenoceptors, has a marginal chance of alleviating
the IL-1β-evoked IL-6 release [72]. The above discussion signifies that more work needs to
be done to accurately identify the molecular mechanisms.
DEXM not only reduces IL-β and IL-6 but also other pro-inflammatory cytokines such
as TNF-α and NF-κB [74,75]. Meanwhile, the α2 receptor on the medulla oblongata is
stimulated by DEXM, which alleviates the Sympathetic Nervous System (SNS) and domi-
nant Parasympathetic Nervous System (PNS). Moreover, DEXM significantly decreases
systemic cytokine levels in association with an enhancement in the discharge frequency
of the cervical vagus nerve in response to endotoxin [70,76]. The inflammatory mediators
are not only released by damaged or injured cells but also from supportive cells of the
nervous system. Glial cells are the supportive cells of the nervous system that include
oligodendrocytes, astrocytes, ependymal cells, and microglia. Glial cells not only help in
neuronal repair but also support regeneration and maintain migration hemostasis and
BBB. Astrocytes perform a complex function in both healthy and diseased cells of the
nervous system.
On this basis, they are divided into good and bad astrocytes. Data studies reported
that DEXM influences inhibitory effects by reducing astrocyte overactivation in response
to nerve injury, or ischemic or reperfusion damage. Longitudinal studies also suggest that
DEXM inhibits attenuate inflammatory mediator TNF-α and glial fibrillary acidic protein,
which suggests DEXM has a neuroprotective effect [43]. DEXM and BDNF (Brain-Derived
Neurotrophic Factor) provide a significant neuroprotective effect. DEXM enhances Bdnf4
Brain Sci. 2021, 11, 846 10 of 15

and Bdnf5 transcription and also increases the BDNF in astrocytes through the extracellular
signal-regulated kinase-dependent pathway, subsequently providing neuroprotection. As
BDNF is a neurotrophin found in the healthy and diseased brain and body, evidence
suggests that BNDF is associated with neurotransmitter regulation, neuronal plasticity,
maintenance, and survival [77].
To summarize, DEXM treatment has been observed to eliminate or alleviate neu-
roinflammatory mediators (IL-6, TNF-α, NF-κB) and also increase Bdnf4 and Bdnf5 tran-
scription and BDNF in astrocytes, which ultimately produces its neuroprotective effect, as
summarized in Table 2.

Table 2. Summary of DEXM-associated neuroprotective effects.

References Mechanisms Animal Model Marker DEXM Effect

Neonatal rats randomly allocated ↑ EAAT3 expression, ↓ nerve
[55] Excitotoxicity Glutamate
to 4 groups (n = 36 each) sensitivity for glutamate.
Adult male Sprague Dawley rats
Upregulates anti-apoptotic
[59] randomly allocated to 4 groups Bcl2, FAK
marker
(n = 10 each)
Apoptosis
[17] Adult male C57BL/6 J mice n = 80 MDM2, p53 pathway ↓ p53 activity via Mdm2
Rat glioma C6 cells Cell culture in
Phosphorylates AKT,
[62] Dulbecco’s modified Eagle’s PI3k/AKT
upregulates PI3k expression
Medium (DMEM)
Male Sprague-Dawley rats Upregulates FAK that activates
[61] Caspase 3
n = unknown IAP that attenuate caspase 3
↓ IL-1β induces IL-6 release
Rat C6 glioma cells. Cell culture in IL-1β induces IL-6
[72] Inflammatory independently adenyl cyclase
DMEM release
mediator cAMP pathway
Systemic cytokines
Significantly decreases
[71] Long–Evans female rats TNF-α, NF-kB, IL-1β,
systemic cytokines level
IL-18
Human astrocyte 1321N1 cells and LHD, NLRP3, ASC,
Inhibits NL RP3
[58] Stepsis rat neuron PC12 cells. Cell culture Caspase 1 inducing
inflammasome assembly
in DMEM IL-1β, IL-18
Decrease over activated
[43] Astroglia Astrocytes, Cell culture Astrocytes
astrocytes
Note: “↑” increase and “↓” decrease.

3.5. Clinical Evidence of Dexmedetomidine as Neuroprotective Agent

Some randomized clinical trials that suggested DEXM as a neuroprotective agent are
shown in Table 3. Some randomized clinical trials that suggested DEXM is a neuroprotec-
tive agent are also displayed in Table 2. Xiahong Luo et al. conducted a randomized clinical
trial to explore the neuroprotective efficacy of DEXM. Sixty glioma patients underwent
craniotomy resection, among them thirty patients received IV 1 µg/kg 10 min of DEXM
with a maintenance dose of 0.4 µg/(kg/h). It was found that the DEXM could significantly
reduce serum expression of an inflammatory mediator (TNF α, IL-6), inhibit free radical
generation (superoxide dismutase), and stabilize hemodynamic parameters (Mean arterial
pressure and heart rate) [19]. Xiahong Luo et al. [19] and Ashish Bindra et al. [78] ruled
out the brain injury biomarkers: Neuron-Specific enolase of Enzyme (NSE) (enzyme re-
lease during neuronal injury) and S100b (express by type 2 astrocytes). These biomarkers
cause cerebral insult in chronic temporal lobe epilepsy. Intraoperative DEXM treatment
attenuates S100b and NSE, which suggests its neuroprotective property during epilepsy
surgery [78].
Brain Sci. 2021, 11, 846 11 of 15

Table 3. Randomized clinical trials of Dexmedetomidine as a neuroprotective agent.

Condition Number of Cases Outcome References

Brain protection in patients DEXM stabilized hemodynamics,
undergoing craniotomy resection of 60 cases attenuated inflammation, and inhibited [19]
glioma. the generation of free radicals.
Cerebroprotection during epilepsy
19 cases Treatment with DEXM low S100b level [78]
surgery.
DEXM was neuroprotective in the stroke
Improves cognition after carotid
49 cases model by reducing TNF-α and IL-6 and [71]
endarterectomy.
enhancing BNDF.
Reduce postoperative delirium (POD)
in elderly patients with mild DEXM treatment significantly improved
80 cases [79]
cognitive impairment (MCI) after POD MCI in elderly patients.
joint replacement surgery.
A double-blind, randomized, and DEXM enhances plasma concentrations
40 cases [80]
placebo-controlled study. of BDNF caused by the anesthetic agent.

Brain-Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family,

which has an important role in axonal growth, synaptic plasticity, and neuronal survival.
An elevated level of BDNF in the CNS can protect neurons from ischemic injury [79,80].
A randomized clinical trial suggested that IV DEXM infusion during surgery improves
cognition after carotid endarterectomy by increasing BDNF concentration [71]. It helped
by attenuating the duration of postoperative delirium [79]. The above studies provide a
vital theoretical aspect for the application of DEXM in neuroprotection.

4. Conclusions
This work demonstrates the role of DEXM as a neuroprotective agent, which has been
tested in various experimental models. It has been corroborated from the literature survey
that DEXM abolishes its neuroprotective effects through the upregulation of α2 adrenore-
ceptor. DEXM imidazoline moiety binds with the I2 receptor, which is present on the outer
surface of mitochondria that reduces Ca2+ modulated apoptosis. Moreover, preclinical data
inferred that DEXM considerably decreases neuroinflammation and neurodegeneration
following neurological insult. After a rigorous literature survey on the DEXM drug, the
following decisive concluding remarks can be made:
(i) Clinical investigations of DEXM should be designed to verify the efficacy of different
steps of the cascade of neuronal damage.
(ii) DEXM improves neuroinflammatory behavior by suppressing inflammatory media-
tors. It not only controls apoptotic signaling pathways but also decreases oxygen-free
radical generation.
(iii) The randomized clinical trials on DEXM suggest its ability to enhance BDNF to protect
the brain from ischemic insult.
(iv) DEXM not only improves cognition but also attenuates the duration of postoperative
delirium.
The aforementioned conclusions regarding the neuroprotective agent (DEXM) can
serve as a benchmark for researchers and doctors to substantiate DEXM’s efficacy in
exerting anti-inflammatory properties that ameliorate and prevent nerve injuries. However,
many areas are yet to be explored, for instance, certain extended applications of DEXM
require further evaluation to ensure the safe use of DEXM before it is designed in a clinical
trial. It is imperative to carefully select patients and to determine the appropriate dosage,
as DEXM usage is still limited in the pediatric population.
Brain Sci. 2021, 11, 846 12 of 15

Author Contributions: Conceptualization, funding acquisition, resources, and supervision, L.Z. and
R.F., Z.L., P.L.M.Z., and X.X. wrote the manuscript. L.Z. and R.F. reviewed and edited the manuscript.
All authors have read and agreed to the published version of the manuscript.
Funding: This work is made possible by the National Natural Science Foundation of China, grant
number 82071496 to R.F., the Young Teacher Foundation of Sun Yat-sen University grant number
59000-18841219 to R.F., and Natural Science Foundation of Guangdong Province grant number
2021A1515010463 to R.F.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or
in the decision to publish the results.

References
1. Park, H.R.; Lee, G.S.; Kim, I.S.; Chang, J.-C. Brachial plexus injury in adults. Nerve 2017, 3, 1–11. [CrossRef]
2. Yannascoli, S.M.; Stwalley, D.; Saeed, M.J.; Olsen, M.A.; Dy, C.J. A population-based assessment of depression and anxiety in
patients with brachial plexus injuries. J. Hand Surg. 2018, 43, 1136.e1–1136.e9. [CrossRef] [PubMed]
3. Levi, M.; Brimble, M. A review of neuroprotective agents. Curr. Med. Chem. 2004, 11, 2383–2397. [CrossRef] [PubMed]
4. Chrysostomou, C.; Schmitt, C.G. Dexmedetomidine: Sedation, analgesia and beyond. Expert Opin. Drug Metab. Toxicol. 2008, 4,
619–627. [CrossRef]
5. Grewal, A. Dexmedetomidine: New avenues. J. Anaesthesiol. Clin. Pharmacol. 2011, 27, 297–302. [CrossRef]
6. Zhang, Q.; Chen, Y.-Q. Advances in the Clinical Use of Dexmedetomidine. Med Recapitul. 2011, 3, 434–437. (In Chinese)
7. Marwaha, A. Anesthesia Considerations for Tracheal Reconstruction. In Clinical Thoracic Anesthesia; Springer: Singapore, 2020;
pp. 181–201.
8. Keating, G.M. Dexmedetomidine: A review of its use for sedation in the intensive care setting. Drugs 2015, 75, 1119–1130.
[CrossRef]
9. Weerink, M.A.; Struys, M.M.; Hannivoort, L.N.; Barends, C.R.; Absalom, A.R.; Colin, P. Clinical pharmacokinetics and pharmaco-
dynamics of dexmedetomidine. Clin. Pharmacokinet. 2017, 56, 893–913. [CrossRef]
10. Elgebaly, A.S.; Sabry, M. Sedation effects by dexmedetomidine versus propofol in decreasing duration of mechanical ventilation
after open heart surgery. Ann. Card. Anaesth. 2018, 21, 235–242. [CrossRef]
11. Deiner, S.; Luo, X.; Lin, H.-M.; Sessler, D.I.; Saager, L.; Sieber, F.E.; Lee, H.B.; Sano, M.; Jankowski, C.; Bergese, S.D. Intraoperative
infusion of dexmedetomidine for prevention of postoperative delirium and cognitive dysfunction in elderly patients undergoing
major elective noncardiac surgery: A randomized clinical trial. JAMA Surg. 2017, 152, e171505. [CrossRef]
12. Zhao, W.; Hu, Y.; Chen, H.; Wang, X.; Wang, L.; Wang, Y.; Wu, X.; Han, F. The Effect and Optimal Dosage of Dexmedetomidine
Plus Sufentanil for Postoperative Analgesia in Elderly Patients with Postoperative Delirium and Early Postoperative Cognitive
Dysfunction: A Single-Center, Prospective, Randomized, Double-Blind, Controlled Trial. Front. Neurosci. 2020, 14, 549516.
13. Lee, S. Dexmedetomidine: Present and future directions. Korean J. Anesthesiol. 2019, 72, 323–330. [CrossRef]
14. Yoshikawa, Y.; Hirata, N.; Kawaguchi, R.; Tokinaga, Y.; Yamakage, M. Dexmedetomidine maintains its direct cardioprotective
effect against ischemia/reperfusion injury in hypertensive hypertrophied myocardium. Anesth. Analg. 2018, 126, 443–452.
[CrossRef]
15. Ma, J.; Chen, Q.; Li, J.; Zhao, H.; Mi, E.; Chen, Y.; Yi, B.; Ning, J.; Ma, D.; Lu, K. Dexmedetomidine-mediated prevention of renal
ischemia-reperfusion injury depends in part on cholinergic anti-inflammatory mechanisms. Anesth. Analg. 2020, 130, 1054–1062.
[CrossRef]
16. Zhu, L.; Zhang, Y.; Zhang, Z.; Ding, X.; Gong, C.; Qian, Y. Activation of PI3K/Akt/HIF-1α signaling is involved in lung protection
of dexmedetomidine in patients undergoing video-assisted thoracoscopic surgery: A pilot study. Drug Des. Dev. Ther. 2020, 14,
5155–5166. [CrossRef]
17. Lv, H.; Li, Y.; Cheng, Q.; Chen, J.; Chen, W. Neuroprotective Effects Against Cerebral Ischemic Injury Exerted by Dexmedetomidine
via the HDAC5/NPAS4/MDM2/PSD-95 Axis. Mol. Neurobiol. 2021, 58, 1990–2004. [CrossRef]
18. Anttila, M.; Penttilä, J.; Helminen, A.; Vuorilehto, L.; Scheinin, H. Bioavailability of dexmedetomidine after extravascular doses in
healthy subjects. Br. J. Clin. Pharmacol. 2003, 56, 691–693. [CrossRef]
19. Luo, X.; Zheng, X.; Huang, H. Protective effects of dexmedetomidine on brain function of glioma patients undergoing craniotomy
resection and its underlying mechanism. Clin. Neurol. Neurosurg. 2016, 146, 105–108. [CrossRef]
20. Gertler, R.; Brown, H.C.; Mitchell, D.H.; Silvius, E.N. Dexmedetomidine: A novel sedative-analgesic agent. Bayl. Univ. Med Cent.
Proc. 2001, 14, 13–21. [CrossRef]
Brain Sci. 2021, 11, 846 13 of 15

21. Colin, P.; Hannivoort, L.N.; Eleveld, D.J.; Reyntjens, K.M.; Absalom, A.R.; Vereecke, H.E.; Struys, M.M. Dexmedetomidine
pharmacodynamics in healthy volunteers: 2. Haemodynamic profile. BJA Br. J. Anaesth. 2017, 119, 211–220. [CrossRef]
22. Mantz, J. Dexmedetomidine. Drugs Today 1999, 35, 151–157. [CrossRef]
23. Yu, S.-B. Dexmedetomidine sedation in ICU. Korean J. Anesthesiol. 2012, 62, 405–411. [CrossRef]
24. Naik, B.I.; Nemergut, E.C.; Kazemi, A.; Fernández, L.; Cederholm, S.K.; McMurry, T.L.; Durieux, M.E. The effect of dexmedetomi-
dine on postoperative opioid consumption and pain after major spine surgery. Anesth. Analg. 2016, 122, 1646–1653. [CrossRef]
25. Ling, X.; Zhou, H.; Ni, Y.; Wu, C.; Zhang, C.; Zhu, Z. Does dexmedetomidine have an antiarrhythmic effect on cardiac patients? A
meta-analysis of randomized controlled trials. PLoS ONE 2018, 13, e0193303. [CrossRef] [PubMed]
26. Botero Posada, L.F.; Arias Jiménez, J.M.; Vasseur Arboleda, J.P. The use of dexmedetomidine (DXM) for implanting a cardiac
resynchronization device: Is it really safe? Colomb. J. Anestesiol. 2011, 39, 425–431. [CrossRef]
27. Seyrek, M.; Halici, Z.; Yildiz, O.; Ulusoy, H.B. Interaction between dexmedetomidine and α-adrenergic receptors: Emphasis on
vascular actions. J. Cardiothorac. Vasc. Anesth. 2011, 25, 856–862. [CrossRef]
28. Afonso, J.; Reis, F. Dexmedetomidine: Current role in anesthesia and intensive care. Braz. J. Anesthesiol. 2012, 62, 118–133.
[CrossRef]
29. Murrell, J.C.; Hellebrekers, L.J. Medetomidine and dexmedetomidine: A review of cardiovascular effects and antinociceptive
properties in the dog. Vet. Anaesth. Analg. 2005, 32, 117–127. [CrossRef]
30. Arcangeli, A.; D’alo, C.; Gaspari, R. Dexmedetomidine use in general anaesthesia. Curr. Drug Targets 2009, 10, 687–695. [CrossRef]
31. Bylund, D.B. Subtypes of α1-and α2-adrenergic receptors. FASEB J. 1992, 6, 832–839. [CrossRef]
32. Ciccarelli, M.; Sorriento, D.; Coscioni, E.; Iaccarino, G.; Santulli, G. Adrenergic receptors. Endocrinol. Heart Health Dis. 2017,
285–315.
33. Kim, H.; Choi, S.-H.; Ha, S.-H.; Chang, W.-S.; Heo, G.-A.; Jeong, J.; Min, K.T. Haemodynamic changes and incisional bleeding
after scalp infiltration of dexmedetomidine with lidocaine in neurosurgical patients. Anaesth. Crit. Care Pain Med. 2019, 38,
237–242. [CrossRef] [PubMed]
34. Yuan, D.; Liu, Z.; Kaindl, J.; Maeda, S.; Zhao, J.; Sun, X.; Xu, J.; Gmeiner, P.; Wang, H.-W.; Kobilka, B.K. Activation of the α 2B
adrenoceptor by the sedative sympatholytic dexmedetomidine. Nat. Chem. Biol. 2020, 16, 507–512. [CrossRef] [PubMed]
35. Ma, D.; Hossain, M.; Rajakumaraswamy, N.; Arshad, M.; Sanders, R.D.; Franks, N.P.; Maze, M. Dexmedetomidine produces its
neuroprotective effect via the α2A-adrenoceptor subtype. Eur. J. Pharmacol. 2004, 502, 87–97. [CrossRef]
36. Zhang, Y.; Kimelberg, H.K. Neuroprotection by alpha 2-adrenergic agonists in cerebral ischemia. Curr. Neuropharmacol. 2005, 3,
317–323. [CrossRef]
37. De Vos, H.; Vauquelin, G.; De Keyser, J.; De Backer, J.P.; Van Liefde, I. Regional Distribution of α2A-and α2B-Adrenoceptor
Subtypes in Postmortem Human Brain. J. Neurochem. 1992, 58, 1555–1560. [CrossRef]
38. Scheinin, M.; Lomasney, J.W.; Hayden-Hixson, D.M.; Schambra, U.B.; Caron, M.G.; Lefkowitz, R.J.; Fremeau Jr, R.T. Distribution
of α2-adrenergic receptor subtype gene expression in rat brain. Mol. Brain Res. 1994, 21, 133–149. [CrossRef]
39. Sinclair, M.D. A review of the physiological effects of α2-agonists related to the clinical use of medetomidine in small animal
practice. Can. Vet. J. 2003, 44, 885–897.
40. Ruffolo Jr, R.R.; Stadel, J.M.; Hieble, J.P. α-adrenoceptors: Recent developments. Med. Res. Rev. 1994, 14, 229–270. [CrossRef]
41. Khan, Z.; Ferguson, C.; Jones, R. Alpha-2 and imidazoline receptor agonistsTheir pharmacology and therapeutic role. Anaesthesia
1999, 54, 146–165. [CrossRef]
42. Bousquet, P.; Hudson, A.; García-Sevilla, J.A.; Li, J.-X. Imidazoline receptor system: The past, the present, and the future.
Pharmacol. Rev. 2020, 72, 50–79. [CrossRef]
43. Janke, E.L.; Samra, S. Dexmedetomidine and neuroprotection. Semin. Anesth. Perioper. Med. Pain 2006, 25, 71–76. [CrossRef]
44. Inagaki, M.; Somei, M.; Oguchi, T.; Ono, R.; Fukutaka, S.; Matsuoka, I.; Tsuji, M.; Oguchi, K. Neuroprotective Effects of
Dexmedetomidine against-induced ER-stress via Activity of α2-adrenoceptors and Imidazoline Receptors. AIMS Neurosci. 2016,
3, 237–252. [CrossRef]
45. Takamatsu, I.; Iwase, A.; Ozaki, M.; Kazama, T.; Wada, K.; Sekiguchi, M. Dexmedetomidine reduces long-term potentiation in
mouse hippocampus. J. Am. Soc. Anesthesiol. 2008, 108, 94–102. [CrossRef]
46. D’Arcy, M.S. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol. Int. 2019, 43, 582–592.
[CrossRef]
47. Süudhof, T.C. Neurotransmitter release. In Pharmacology of Neurotransmitter Release; Springer: Berlin, Germany, 2008; pp. 1–21.
48. Südhof, T.C. Calcium control of neurotransmitter release. Cold Spring Harb. Perspect. Biol. 2012, 4, a011353. [CrossRef]
49. Degos, V.; Charpentier, T.L.; Chhor, V.; Brissaud, O.; Lebon, S.; Schwendimann, L.; Bednareck, N.; Passemard, S.; Mantz, J.;
Gressens, P. Neuroprotective effects of dexmedetomidine against glutamate agonist-induced neuronal cell death are related to
increased astrocyte brain-derived neurotrophic factor expression. Anesthesiology 2013, 118, 1123–1132. [CrossRef]
50. Zhao, Y.; He, J.; Yu, N.; Jia, C.; Wang, S. Mechanisms of dexmedetomidine in neuropathic pain. Front. Neurosci. 2020, 14, 330.
[CrossRef]
51. Noch, E.; Khalili, K. Molecular mechanisms of necrosis in glioblastoma: The role of glutamate excitotoxicity. Cancer Biol. Ther.
2009, 8, 1791–1797. [CrossRef]
52. Ji, X.; Guo, Y.; Zhou, G.; Wang, Y.; Zhang, J.; Wang, Z.; Wang, Q. Dexmedetomidine protects against high mobility group box
1-induced cellular injury by inhibiting pyroptosis. Cell Biol. Int. 2019, 43, 651–657. [CrossRef]
Brain Sci. 2021, 11, 846 14 of 15

53. Chiu, K.-M.; Lin, T.-Y.; Lu, C.-W.; Wang, S.-J. Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by α2
adrenoceptor agonist dexmedetomidine. Eur. J. Pharmacol. 2011, 670, 137–147. [CrossRef] [PubMed]
54. Do, S.-H.; Park, S.-J.; Shin, H.-J.; Paik, H.-S.; Zuo, Z.; Yoon, H.-J.; Ryu, J.-H. Dexmedetomidine increases the activity of excitatory
amino acid transporter type 3 expressed in Xenopus oocytes: The involvement of protein kinase C and phosphatidylinositol
3-kinase. Eur. J. Pharmacol. 2014, 738, 8–13. [CrossRef] [PubMed]
55. Wang, X.; Shan, Y.; Tang, Z.; Gao, L.; Liu, H. Neuroprotective effects of dexmedetomidine against isoflurane-induced neuronal
injury via glutamate regulation in neonatal rats. Drug Des. Dev. Ther. 2019, 13, 153–160. [CrossRef] [PubMed]
56. Peng, M.; Ling, X.; Song, R.; Gao, X.; Liang, Z.; Fang, F.; Cang, J. Upregulation of GLT-1 via PI3K/Akt pathway contributes to
neuroprotection induced by dexmedetomidine. Front. Neurol. 2019, 10, 1041. [CrossRef] [PubMed]
57. Sun, Y.; Zhao, H.; Wang, D.; Ma, D. Dexmedetomidine alleviates LPS-induced pyroptosis in astrocytes in vitro. Br. J. Anaesth.
2018, 120, e8–e9. [CrossRef]
58. Sun, Y.-B.; Zhao, H.; Mu, D.-L.; Zhang, W.; Cui, J.; Wu, L.; Alam, A.; Wang, D.-X.; Ma, D. Dexmedetomidine inhibits astrocyte
pyroptosis and subsequently protects the brain in in vitro and in vivo models of sepsis. Cell Death Dis. 2019, 10, 167. [CrossRef]
59. Han, J.-H.; Kim, D.-O.; Yi, J.-W.; Park, S.-W.; Kang, W.-J.; Choi, Y.-K.; Kim, S.-H.; Ko, I.-G.; Jin, J.-J.; Kim, S.-E. Dexmedetomidine,
α2-adrenoceptor agonist, does not induce apoptosis in the brachial plexus of rats. Anim. Cells Syst. 2014, 18, 407–415. [CrossRef]
60. Thomasova, D.; Bruns, H.A.; Kretschmer, V.; Ebrahim, M.; Romoli, S.; Liapis, H.; Kotb, A.M.; Endlich, N.; Anders, H.-J. Murine
double minute-2 prevents p53-overactivation-related cell death (podoptosis) of podocytes. J. Am. Soc. Nephrol. 2015, 26, 1513–1523.
[CrossRef]
61. Dahmani, S.; Rouelle, D.; Gressens, P.; Mantz, J. Effects of dexmedetomidine on hippocampal focal adhesion kinase tyrosine
phosphorylation in physiologic and ischemic conditions. J. Am. Soc. Anesthesiol. 2005, 103, 969–977. [CrossRef]
62. Zhang, F.; Ding, T.; Yu, L.; Zhong, Y.; Dai, H.; Yan, M. Dexmedetomidine protects against oxygen–glucose deprivation-induced
injury through the I2 imidazoline receptor-PI3K/AKT pathway in rat C6 glioma cells. J. Pharm. Pharmacol. 2012, 64, 120–127.
[CrossRef]
63. Ding, X.-D.; Zheng, N.-N.; Cao, Y.-Y.; Zhao, G.-Y.; Zhao, P. Dexmedetomidine preconditioning attenuates global cerebral ischemic
injury following asphyxial cardiac arrest. Int. J. Neurosci. 2016, 126, 249–256. [CrossRef]
64. Pugliese, A.M.; Latini, S.; Corradetti, R.; Pedata, F. Brief, repeated, oxygen-glucose deprivation episodes protect neurotransmission
from a longer ischemic episode in the in vitro hippocampus: Role of adenosine receptors. Br. J. Pharmacol. 2003, 140, 305–314.
[CrossRef]
65. Shen, M.; Wang, S.; Wen, X.; Han, X.-R.; Wang, Y.-J.; Zhou, X.-M.; Zhang, M.-H.; Wu, D.-M.; Lu, J.; Zheng, Y.-L. Dexmedetomidine
exerts neuroprotective effect via the activation of the PI3K/Akt/mTOR signaling pathway in rats with traumatic brain injury.
Biomed. Pharmacother. 2017, 95, 885–893. [CrossRef]
66. Zhu, Y.-M.; Wang, C.-C.; Chen, L.; Qian, L.-B.; Ma, L.-L.; Yu, J.; Zhu, M.-H.; Wen, C.-Y.; Yu, L.-N.; Yan, M. Both PI3K/Akt and
ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury
in rats. Brain Res. 2013, 1494, 1–8. [CrossRef]
67. Wang, K.; Zhu, Y. Dexmedetomidine protects against oxygen-glucose deprivation/reoxygenation injury-induced apoptosis via
the p38 MAPK/ERK signalling pathway. J. Int. Med Res. 2018, 46, 675–686. [CrossRef]
68. Tanabe, K.; Kozawa, O.; Iida, H. Midazolam suppresses interleukin-1β-induced interleukin-6 release from rat glial cells. J.
Neuroinflamm. 2011, 8, 68. [CrossRef]
69. Tanabe, K.; Kozawa, O.; Iida, H. cAMP/PKA enhances interleukin-1β-induced interleukin-6 synthesis through STAT3 in glial
cells. Cell. Signal. 2016, 28, 19–24. [CrossRef]
70. Zhu, Y.-J.; Peng, K.; Meng, X.-W.; Ji, F.-H. Attenuation of neuroinflammation by dexmedetomidine is associated with activation of
a cholinergic anti-inflammatory pathway in a rat tibial fracture model. Brain Res. 2016, 1644, 1–8. [CrossRef]
71. Ge, Y.; Li, Q.; Nie, Y.; Gao, J.; Luo, K.; Fang, X.; Wang, C. Dexmedetomidine improves cognition after carotid endarterectomy by
inhibiting cerebral inflammation and enhancing brain-derived neurotrophic factor expression. J. Int. Med Res. 2019, 47, 2471–2482.
[CrossRef]
72. Tanabe, K.; Matsushima-Nishiwaki, R.; Kozawa, O.; Iida, H. Dexmedetomidine suppresses interleukin-1β-induced interleukin-6
synthesis in rat glial cells. Int. J. Mol. Med. 2014, 34, 1032–1038. [CrossRef]
73. Zhang, X.; Wang, J.; Qian, W.; Zhao, J.; Sun, L.; Qian, Y.; Xiao, H. Dexmedetomidine inhibits tumor necrosis factor-alpha and
interleukin 6 in lipopolysaccharide-stimulated astrocytes by suppression of c-Jun N-terminal kinases. Inflammation 2014, 37,
942–949. [CrossRef] [PubMed]
74. Kim, E.; Kim, H.-C.; Lee, S.; Ryu, H.-G.; Park, Y.-H.; Kim, J.H.; Lim, Y.-J.; Park, H.-P. Dexmedetomidine confers neuroprotection
against transient global cerebral ischemia/reperfusion injury in rats by inhibiting inflammation through inactivation of the
TLR-4/NF-κB pathway. Neurosci. Lett. 2017, 649, 20–27. [CrossRef] [PubMed]
75. Wang, L.; Liu, H.; Zhang, L.; Wang, G.; Zhang, M.; Yu, Y. Neuroprotection of dexmedetomidine against cerebral ischemia-
reperfusion injury in rats: Involved in inhibition of NF-κB and inflammation response. Biomol. Ther. 2017, 25, 383–389. [CrossRef]
[PubMed]
76. Xiang, H.; Hu, B.; Li, Z.; Li, J. Dexmedetomidine controls systemic cytokine levels through the cholinergic anti-inflammatory
pathway. Inflammation 2014, 37, 1763–1770. [CrossRef]
Brain Sci. 2021, 11, 846 15 of 15

77. Giacobbo, B.L.; Doorduin, J.; Klein, H.C.; Dierckx, R.A.; Bromberg, E.; de Vries, E.F. Brain-derived neurotrophic factor in brain
disorders: Focus on neuroinflammation. Mol. Neurobiol. 2019, 56, 3295–3312. [CrossRef]
78. Bindra, A.; Kaushal, A.; Prabhakar, H.; Chaturvedi, A.; Chandra, P.S.; Tripathi, M.; Subbiah, V.; Sathianathan, S.; Banerjee, J.;
Prakash, C. Neuroprotective role of dexmedetomidine in epilepsy surgery: A preliminary study. Neurol. India 2019, 67, 163–168.
[CrossRef]
79. Liu, Y.; Ma, L.; Gao, M.; Guo, W.; Ma, Y. Dexmedetomidine reduces postoperative delirium after joint replacement in elderly
patients with mild cognitive impairment. Aging Clin. Exp. Res. 2016, 28, 729–736. [CrossRef]
80. Yang, L.; Xu, J.-M.; Jiang, X.; Ruan, W.; Cui, Y.; He, L. Effect of dexmedetomidine on plasma brain-derived neurotrophic factor: A
double-blind, randomized and placebo-controlled study. Upsala J. Med Sci. 2013, 118, 235–239. [CrossRef]