2.3.1 MicroRNA
MicroRNAs can be detected in biological fluids, making them potential
diagnostic biomarkers, which have been reported as biomarkers for the
diagnosis of epilepsy. Meanwhile, microRNA, as an emerging therapeutic
target, provides unique therapeutic advantages for some epilepsy with
complex pathophysiological mechanisms by negatively regulating related
proteins(Morris et al., 2021). Currently, many microRNAs are
consistently dysregulated in epilepsy and affect seizures, which are
also described as biomarkers for the diagnosis of TLE and predictive
biomarkers for AED response(Mooney et al., 2016; De Benedittis et al.,
2021) (Table1) .
Related studies have found that microRNAs are significantly upregulated
in epilepsy. MicroRNA-20a-5p is involved in synaptic plasticity and
silencing microRNA-20a-5p inhibits neuronal branching and axonal growth
and prevents epileptogenesis by regulating RGMa-RhoA-mediated synaptic
plasticity in the PTZ-induced epilepsy model(Feng et al., 2020).
MicroRNA-21-5p reduces IL-6 levels, loss of hippocampal neurons and
apoptosis by inhibiting STAT3 expression, which suggesting protective
effects of microRNA-21-5p in hippocampal neurons of epileptic rats(Zhang
et al., 2020). In KA-induced SE models, targeting of microRNA-21-5p also
protects against seizure-induced injury by PTEN-mTOR (Tang et al.,
2018). MicroRNA-23a is involved in hippocampal neuron injury,
hippocampal oxidative damage and impairment of spatial memory in
KA-induced TLE mice(Zhu et al., 2019b). Meanwhile, microRNA-23a can also
regulate ADAM10, which contributes to epileptogenesis in
pilocarpine-induced SE mice(Zhu et al., 2019a). MicroRNA-27a-3p
regulates ion channel-related DEGs in multiple mTLE and downregulation
of microRNA-27a-3p inhibits apoptosis of hippocampal neurons and
inflammatory response by upregulating MAP2K4 in KA-induced epilepsy
models(Lu et al., 2019; Su et al., 2022b). Inhibition of microRNA-103a
regulates BDNF to improve neuron injury and inhibit activated astrocytes
in pilocarpine-induced epilepsy rat models(Zheng et al., 2019).
Depletion of microRNA-132 can reduce seizure-induced neuronal death in
KA-induced epilepsy mice models and microRNA-132 can suppress BDNF/TrkB
signaling to aggravate epileptiform discharges in the
Mg2+-free treated hippocampal neuronal model of
SE(Jimenez-Mateos et al., 2011; Xiang et al., 2015). Meanwhile,
microRNA-132 also reduces the expression of pro-epileptogenic factors
(COX-2, IL-1β, TGF-β2, CCL2 and MMP3) in human cultured astrocytes of
TLE(Korotkov et al., 2020). Inhibition of microRNA-134 can effectively
reduce the occurrence of spontaneous recurrent seizures and silencing
microRNA-134 can produce neuroprotective, reducing the severity of
seizures in KA-induced epilepsy mice model(Jimenez-Mateos et al., 2012;
Morris et al., 2019). MicroRNA-134 inhibits the expression of
cAMP-response element binding protein (CREB) and p-CREB to regulate
synaptic plasticity in pilocarpine-induced epilepsy rat model(Zhu et
al., 2015). Antagonizing microRNA-135a can reduce spontaneous recurrent
seizures to affect synaptic function and plasticity by targeting Mef2a
in KA-induced epilepsy mice model. And inhibition of microRNA-135a
protects glial cells against apoptosis by regulating SIRT1-related
signaling pathway in KA-induced BV2
microglia epilepsy model(Vangoor et al., 2019; Wang et al., 2021c).
Inhibition of microRNA-141 can inhibit P53 to protect against apoptosis
by SIRT1 expression
in
KA-induced epilepsy rat model(Liu et al., 2019a). MicroRNA-142 performs
well in differentiating between drug-resistant and drug-sensitive TLE.
Inhibition of microRNA-142 promotes mitochondrial autophagy and reduces
hippocampal neuron damage by targeting PINK1 in pilocarpine-induced
epilepsy rat model(Xiao et al., 2021). Downregulation of microRNA-145
improves the abilities of learning and memory by reducing apoptosis of
hippocampal neurons in pilocarpine-induced epilepsy rat model(Zhao et
al., 2019a). MicroRNA-146a is a powerful regulator of microglia-mediated
inflammation in the chronic
TLE(Aronica et al., 2010; Su et
al., 2016). MicroRNA-146a-CFH-IL-1β loop circuit mediates the perpetuate
inflammation of chronic TLE in
KA-induced epilepsy rat model and antagonists targeting microRNA-146a
can also protect against SE by regulating NF-κB
pathway in pilocarpine-induced
epilepsy rat model(Li et al., 2018c; Zhang et al., 2018a). In addition,
microRNA-146a can ameliorate dysregulation of the MMP/TIMP proteolytic
system in TSC(Broekaart et al.,
2020). Febrile seizure(FS)-related microRNA-148a-3p plays
neuroprotective roles by increasing the proliferation of hippocampal
neurons in Mg2+ -free medium treated TLE cell model(Yu
et al., 2021). MicroRNA-155 is involved in epileptogenesis by the
PI3K/Akt/mTOR signaling pathway(Duan et al., 2018). Meanwhile,
inhibition of microRNA-155 attenuates MMP3 expression in cultured human
astrocytes, increases the expression of BDNF and alleviates seizure
severity in the pilocarpine-induced epilepsy, and attenuates KA-induced
seizure by inhibiting microglia activation(Cai et al., 2016; Korotkov et
al., 2018; Fu et al., 2019). MicroRNA-181b can inhibit P38/JNK signaling
pathway by targeting TLR4, thereby reducing apoptosis and autophagy in
KA-induced
epilepsy
rat model(Wang et al., 2019b). However, inhibition of microRNA-181a-5p
also activates SIRT1 to reduce neuronal apoptosis, neuroinflammation,
oxidative stress, cognitive dysfunction and activation of astrocyte and
microglia in pilocarpine-induced epilepsy rat model(Kong et al., 2020).
Downregulated microRNA-183 results in an inactivation of JAK/STAT
signaling pathway by targeting Foxp1 to promote neuron proliferation and
inhibit apoptosis of hippocampal neurons, thereby attenuating
hippocampal neuron injury in pilocarpine-induced epilepsy rat model(Feng
et al., 2019). MicroRNA-187-3p is upregulated and regulates
KCNK10/TREK-2 potassium channel in electrical stimulation-induced
SE(Haenisch et al., 2016). MicroRNA-194-5p regulates the proliferation
and apoptosis of hippocampus neuron in children with TLE and
Mg2+ -free medium treated epilepsy cell model (Niu et
al., 2021). Targeting of microRNA-199a-5p protects against neuron damage
by SIRT1-p53 cascade in pilocarpine-induced epilepsy rat model (Wang et
al., 2016a). Downregulation of microRNA-200c-3p upregulates RECK and
inactivates the AKT signaling to decrease apoptosis of hippocampal
neuron
in
pilocarpine-induced epilepsy rat model(Du et al., 2019). MicroRNA-203 is
targeted to Ppp2ca in both humans and mice, which can target Ppp2ca to
increase seizure activity in the KA-induced SE model(Zhang et al.,
2018b). And microRNA-203 antagomirs can targets glycine receptor-β(GLRB)
to decrease the frequency of spontaneous seizures in pilocarpine-induced
mice epilepsy(Lee et al., 2017). MicroRNA-219 regulates NMDARs in the
amygdala and hippocampus of patients with mTLE and also suppresses
seizure formation by regulating the CaMKII/NMDAR pathway in KA-induced
epilepsy mice model(Zheng et al., 2016; Hamamoto et al., 2020).
MicroRNA-223 also have the good performance in distinguishing
drug-sensitive and drug-resistant TLE and microRNA-223 affects
microglial autophagy by targeting ATG16L1 in TLE(De Benedittis et al.,
2021; He et al., 2021b). MicroRNA-451 regulates GDNF expression to
aggravate hippocampal neuronal apoptosis and seizure in KA-induced
epilepsy mice model(Weng et al., 2020).
Related studies have also found that microRNAs are significantly
downregulated in epilepsy. MicroRNA-15a targets GFAP to inhibit
inflammation and apoptosis of hippocampal neurons by downregulating GFAP
in pilocarpine-induced epilepsy rat model and
Mg2+-free medium treated TLE cell model(Fan et al.,
2020). Propofol regulates microRNA-15a-5p/GluN2B/ERK1/2 pathway to
suppress apoptosis hippocampal neuronal apoptosis in
Mg2+ -free medium treated epilepsy cell model (Liu et
al., 2020). MicroRNA-22 inhibits neuroinflammatory signaling to protect
against the development of epileptogenic brain networks. MicroRNA-22
prevents inflammation and development of epileptogenic focus by
targeting P2X7R in the brain and microRNA-22 regulates aberrant
neurogenesis and changes in neuronal morphology after SE in KA-induced
epilepsy mice model(Jimenez-Mateos et al., 2015; Beamer et al., 2018;
Almeida Silva et al., 2020). MicroRNA-25-3p targets OXSR1 to suppress
oxidative stress and apoptosis of neurons, thereby suppressing
epileptiform discharges in KA-induced epilepsy mice model(Li et al.,
2020). MicroRNA-29a regulates seizure-induced cell death and
inflammation in Mg2+-free medium treated epilepsy cell
model(Wu et al., 2021). Activated microRNA-34a may lead to impaired
corticogenesis in TSC during early brain development and inhibition of
microRNA-34a can regulate apoptosis and Notch signaling to inhibit
epileptiform discharges in Mg2+-free medium treated
epilepsy cell model(Wang et al., 2019a; Korotkov et al., 2021).
Meanwhile, microRNA-34c plays a negative role in seizure and cognitive
function by regulating NMDARs and AMPARs in PTZ-induced epilepsy rat
model(Huang et al., 2018). In addition, decreased microRNA-34c-5p
enhances neuroinflammation to increase loss of hippocampal neuron in DRE
from KA-induced epilepsy mice model and in children with DRE(Fu et al.,
2020). MicroRNA-101a-3p inhibits apoptosis and autophagy by
downregulating c-FOS in pilocarpine-induced epilepsy rat model and
Mg2+-free medium treated epilepsy cell model(Geng et
al., 2021). MicroRNA-124 inhibits some target genes to prevent
upregulation of hippocampal NRSF, which participates in epilepsy and
promotes the activation of hippocampal microglia and inflammatory
cytokines(McClelland et al., 2014; Brennan et al., 2016). MicroRNA-124
suppresses seizure, regulates CREB1 activity, and inhibits neuronal
firing with decreased expression of NMDAR in pilocarpine and PTZ-induced
epilepsy rat model(Wang et al., 2016c). MicroRNA-125a-5p targets CaMK4
to alleviate dysfunction and inflammation in PTZ-induced epilepsy rat
model(Liu et al., 2019b). Inhibition of microRNA-129-2-3p regulates
GABRA1 to protect against refractory TLE in KA-treated primary
hippocampal neurons and KA-induced epilepsy rat model(Wang et al.,
2021a). MicroRNA-129-5p also targets HMGB1 to inhibit the development of
autoimmune encephalomyelitis-related epilepsy by TLR4/NF-kB pathway(Liu
et al., 2017a). MicroRNA-136 inhibits WNT/-Catenin signaling pathway to
play a neuroprotective effect on pilocarpine-induced TLE rats (Cui and
Zhang, 2022). Overexpression of microRNA-137 inhibits seizure activity
in two different epilepsy mouse models (PTZ and pilocarpine) and
suppresses neuronal excitability in Mg2+-free-induced
brain slice model of epileptiform activity(Wang et al., 2018b).
MicroRNA-139-5p negatively regulates GluN2A-NMDAR in pilocarpine-induced
epilepsy rat model and TLE patients and upregulated microRNA-139-5p also
regulates the Notch pathway to reduce spontaneous recurrent epileptiform
discharge-induced apoptosis and oxidative stress in rat primary
hippocampal neurons(Alsharafi et al., 2016; Zhao et al., 2021).
MicroRNA-153 is downregulated in plasma and temporal cortex of mTLE
patients and overexpression of microRNA-153 reduces HIF-1α expression in
rat astrocytes of refractory epilepsy(Li et al., 2016). MicroRNA-204
regulates TrkB-ERK1/2-CREB signaling to inhibit epileptiform discharges
in Mg2+-free medium cultured hippocampal neurons(Xiang
et al., 2016). Dynamic changes of microRNA-211 expression is associated
with epileptiform activity and cholinergic imbalances in murine
forebrain(Bekenstein et al., 2017). MicroRNA-221-3p inhibits HIF-1α to
suppress seizures and microglia activation in the VPA-resistant epilepsy
of KA-induced epilepsy mice model(Fu et al., 2021). MicroRNA-322-5p
regulates the TLR4/TRAF6/NF-κB axis to reduce neuronal inflammation in
pilocarpine-induced epilepsy rat model(Zhou et al., 2022). MicroRNA-344a
regulates seizure-induced apoptosis signaling pathways in PTZ-induced
chronic epilepsy rat model (Liu et al., 2017b). Overexpressed
microRNA-494 inactivates the NF-κB signaling pathway to reduce
hippocampal neuron injury by inhibiting RIPK1 in pilocarpine-induced
epilepsy rat model(Qi et al., 2020). MicroRNA-542-3p suppresses
TLR4/NF-κB signaling pathway to reduce seizure-induced brain injury and
the expression of P-gp in KA-treated primary hippocampal neurons and
KA-induced
epilepsy rat model(Yan et al., 2019). Oddly, microRNA-128 is
significantly downregulated at various phases of TLE development in
epilepsy rat models and TLE patients(Tan et al., 2013; Alsharafi and
Xiao, 2015). However, it has been found that microRNA-128 is upregulated
in KA-induced epilepsy rat model and promotes apoptosis by the SIRT1
cascade in PC12 cells(Chen et al., 2019). MicroRNA-128 can inhibit the
expression of various ion channels and the signaling of ERK2 network
that regulate neuronal
excitability.
Meanwhile, microRNA-128 also inhibits SNAP-25 and SYT1 expression to
regulate epilepsy sensitivity in KA-induced epilepsy mice model(Wang et
al., 2021b). In addition, microRNA-378, microRNA-575, microRNA-629-3p,
microRNA-1202, microRNA-1225-5p, and microRNA-138-5p may also be
diagnostic indicators and predicting surgical prognosis in human
epilepsy(Gattás et al., 2022; Li et al., 2022; Ünalp et al., 2022).
In a word, these novel biomarkers may help to identify new epileptic
treatment targets and contribute to improved epileptic patients’ quality
of life through earlier diagnosis and a more precise prognosis.