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American Journal of  Medical 
Science and Innovation (AJMSI) 

Preclinical Use of  Group I Metabotropic Glutamate Receptors (Group I mGluRs) for 
Ischemic Stroke: Systematic Review and Meta-Analysis

Md. Saidur Rahman1*, Md. Khalid Hasan1, Md. Sajal Khan1

Volume 4 Issue 2, Year 2025
ISSN: 2836-8509 (Online)

DOI: https://doi.org/10.54536/ajmsi.v4i2.6056
https://journals.e-palli.com/home/index.php/ajmsi

Article Information ABSTRACT

Received: September 12, 2025
Accepted: October 10, 2025
Published: November 21, 2025

In ischemic stroke, metabotropic glutamate receptors (mGluRs) have a complex role. Results 
from studies using both agonists and antagonists of  these receptors have been inconsistent. 
This systematic review and meta-analysis assesses multiple preclinical investigations on 
group I mGluR agonists and antagonists. Effect sizes for various outcomes, study quality 
scores, bias risk, and interactions with clinical factors related to functional and histological 
outcomes were analyzed based on relevant papers. Twelve papers covering 41 treatment 
groups of  26 interventions from 1999 to 2023 were included. Twelve studies (25 treatment 
arms) reported structural outcomes, while eight studies (16 treatment arms) reported 
functional outcomes, with a median quality score of  4 out of  10. Expected results showed 
larger effect sizes. The mean effect sizes for neurological score and infarct volume improved 
by -0.75 SMD and -1.37 SMD, respectively, after subgroup adjustments and sensitivity 
analysis. Effect sizes for neuroprotection, neuronal loss, brain temperature, and NMDA 
receptor activity with antagonist treatment were 1.73 SMD, -1.35 SMD, -0.05 SMD, and -0.41 
SMD, respectively. While antagonists significantly (P < 0.05) improved both structural and 
functional outcomes, agonists only improved structural results. However, SYRCLE’s risk-of-
bias tool for animal studies identified potential bias. Additionally, clinical variables such as 
dosage and administration mode of  agonist or antagonist medications influenced the effect 
magnitude. Despite the promising results in preclinical studies, several drugs have failed to 
prevent ischemic stroke in human clinical trials. Future research using animal models of  
stroke is recommended to improve study quality, validity, and reduce the risk of  bias.

Keywords
Agonist, Antagonist, Group 
I mGluRs, Ischemic Stroke, 
Preclinical Studies

1 Department of  Anatomy and Histology, Faculty of  Animal Science and Veterinary Medicine, Patuakhali Science and Technology 
 University, Bangladesh 
* Corresponding author’s e-mail: saidur@pstu.ac.bd

INTRODUCTION
Stroke is one of  the leading causes of  death and 
disability in developed nations (Macarena et al., 2017). 
A damaged or clogged blood vessel stops the flow of  
blood to a portion of  the brain, causing dysfunction 
in the affected area. There isn’t a treatment that works 
well enough to enhance clinical recovery following a 
stroke at the moment. Although it may raise the risk of  
cerebral hemorrhage, tissue plasminogen activator (tPA) 
is important in the early stages of  ischemia (Ning et al., 
2010). Restorative therapy, such as group I metabotropic 
glutamate receptors (mGluRs) blockers and/or activators, 
may help lessen neurological impairment. In pathological 
situations, group I mGluRs, which comprise two subtypes, 
mGluR1 and mGluR5, are intriguing targets for treatment 
in neurodegeneration and acute and chronic traumas. It 
has been demonstrated that mGluR1 antagonists reduce 
neuronal mortality following brain trauma in vivo and 
mechanical injury in vitro. Group I mGluRs antagonists 
have also been found to have a neuroprotective effect in 
ischemic stroke (Faden et al., 2001; Kinga et al., 2007). 
Although some publications noted that both agonists and 
antagonists of  the mGluR5 receptor are neuroprotective, 
no positive effects of  the mGluR5 agonist were observed 
in a model of  endothelin-1-induced localized ischemia in 
rats (Riek-Burchardt et al., 2007; Bao et al., 2001). In addition 
to being linked to new neurons, mGluR5 antagonists are 

also anticipated to alter the milieu of  sick tissue (Norio 
et al., 2012). Because agonists of  these receptors have 
been shown to either increase or decrease neuronal cell 
death, and antagonists of  these receptors are consistently 
neuroprotective, the function of  group I mGluRs in 
animal models of  ischemia is still debatable (Nicoletti et 
al., 1999). Both endogenous and exogenous sources may 
offer viable treatments for ischemic stroke. However, it 
has been shown that endogenous neuro-regeneration is 
not enough to restore damaged brain tissue (Lee et al., 
2011; Minger et al., 2007). Group I mGluRs agonist and/
or antagonist exogenous therapy for ischemic stroke 
has been successfully implemented, according to several 
studies (Bao et al., 2001; Hailong et al., 2013; Dorota et al., 
2006; Elena et al., 2002). The findings showed that group 
I mGluRs agonists and/or antagonists may considerably 
aid in the restoration of  brain tissue and neuro-functional 
outcomes. It is anticipated that the agonist and antagonist 
of  group I mGluRs would mediate homeostasis and 
tissue healing by controlling the release of  brain trophic 
factors or by interacting with immune cells that live in and 
infiltrate the central nervous system. 
A statistical summary of  the findings is called a meta-
analysis (Nordmann et al., 2012; O’Rourke, 2007). The 
estimation of  the extent of  effect is improved and 
ambiguity is resolved by combining the data of  several 
studies using a statistical method rather than relying 



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just on individual studies (Walker et al., 2008). A global 
estimate of  the effectiveness of  medication treatment 
in preclinical stroke models is limited, but there are 
several research and interventional techniques for the 
use of  agonists and antagonists of  group I mGluRs in 
experimental stroke. Thus, the current study’s goal was 
to assess group I mGluRs’ potential as a treatment for 
ischemic stroke in preclinical research. 

MATERIALS AND METHODS
Search Strategy
The publications were looked up using the Science 
Citation Index, ISI Web of  Science, and PubMed for 
animal models of  ischemic stroke until December 2023. 
The literature review was conducted using the PRISMA 
flow diagram and guidelines (Figure 1). The supporting 
information (Table 1) describes the search strategy. 
The featured publications were authored exclusively in 
English. Studies that used hemorrhagic stroke models 
instead of  ischemic ones, transgenic studies, neonatal 
hypoxia/ischemia models, and in vitro research were 
excluded. By looking at the parent institution, sample size, 
author list, and outcome, reports of  duplicate research 
were eliminated. Lastly, trials in which the mGluR agonist 
or antagonist interacted with other biological effects, 
including gene alteration, or in which the therapies 
were administered with monitored imaging instead of  
enhancing outcomes, were not included.

Data Extraction
Authors, year of  publication, type of  intervention (agonist 
and antagonist), animal species, cerebral ischemia type, 
intervention dose, duration of  administration, delivery 
route, anesthetic used, outcome assessment (structural 
and functional), outcome measure used, mean outcome, 
SD (standard deviation) or SE (standard error), number 
of  animals per group, study quality, and risk of  bias 
assessment were among the data we extracted (Tables 
2–5). The outcome in the control (vehicle) group, as 
opposed to the treated group, is what we referred to 
as the treatment comparison. We considered multiple 
interventions to be another intervention if  more than one 
intervention and treatment duration were provided in a 
single research. Additionally, we regarded the efficacious 
doses at a specific time of  administration as a distinct 
treatment arm if  the same intervention was delivered in 
numerous doses. Furthermore, we only took into account 
the infarct volume from the greatest infarct in control 
slices and the smallest infarct in the experimental group 
if  data from several brain slices were given in structural 
results. Another intervention was the assessment of  infarct 
volume throughout varying treatment durations. Lastly, 
only the lowest neurological score for a given treatment 
period was included if  functional outcomes were recorded 
for more than one time point. Every available source, 
including text and figures, was used to extract quantitative 
data for each study. We used quantitative techniques on 
highly magnified images to measure mean and SD/SEM 

values from graphs when the data were solely displayed 
graphically (GetData Graph Digitizer, version 2.26.0.20).

Quality Assessment
The Quality Score evaluation method reviewed the 
checklist of  animal data from experimental studies (Lees 
et al., 2012; Vu et al., 2014) and established 10 criteria 
based on STAIR guidelines (Landis et al., 2012; Fisher et 
al., 2009; Macleod et al., 2004) for each preclinical study 
included in the meta-analysis. (1) publication in a peer-
reviewed journal; (2) statements explaining temperature 
control; (3) random assignment of  animals to treatment 
group; (4) allocation concealment; (5) blinded outcome 
assessment; (6) avoidance of  anesthetics with known 
marked intrinsic neuro-protective properties; (7) use of  
animals with pertinent comorbidities; (8) inclusion of  
a sample-size calculation; (9) statement of  compliance 
with animal welfare regulations; and (10) inclusion of  
a statement declaring the presence or absence of  any 
conflicts of  interest. Each reported criterion was worth 
one point. Higher scores indicate better methodological 
rigor; the potential score goes from 0 to 10 (Chen et al., 
2016). 

Risk of  Bias Assessment
Using SYRCLE’s risk of  bias tool for animal studies, two 
reviewers independently evaluated the risk of  bias, such 
as systematic mistakes (Hooijmans et al., 2014). There 
are ten entries in this animal research tool. The items in 
the Cochrane Risk of  Bias tool agreed with half  of  the 
items. The majority of  the discrepancies between the two 
instruments resulted from the design differences between 
animal research and RCTs.

Data Analysis
The improvement in outcome in treated (intervention) 
animals compared to untreated ischemia (control) 
groups was used to calculate the endpoint effect size 
of  group I mGluRs agonist and/or antagonist therapy. 
Review Manager 5.3 was the program utilized for the 
meta-analysis of  outcome measures. Because there was 
significant heterogeneity across treatment doses and 
time points, we employed the random effect model 
(Borenstein et al., 2010) for the meta-analysis. To report 
the improvement in treated groups, we used the inverse-
variance (IV) technique approach in units of  SD to assess 
significance and the mean effect size using standardized 
mean difference (SMD) with a 95% confidence interval 
(CI) for all included outcomes. A meta-analysis was 
conducted using the effect size of  various doses and 
time points. Results that were expected to decrease were 
employed at the left graph level as an experiment and 
the right graph level as a control; however, the opposite 
was true for results that were expected to increase. We 
regarded it as an additional treatment group to estimate 
efficacy if  more than one structural or functional result 
was reported for the same cohort of  animals at the same 
time point or at a different time point. Sensitivity analysis 



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was then used to identify the treatment arms that were 
not appropriate and to ascertain the heterogeneities of  
the remaining studies. This method can determine why 

other estimates in strata were considerably different and 
examine if  studies were taken from a homogeneous 
population.

Figure 1: PRISMA Flow Diagram showing summary of  study selection procedure.

RESULTS AND DISCUSSION
Study Characteristics
12 out of  1899 papers and 41 treatment groups comprising 
26 distinct interventions (5 agonist and 21 antagonist) 
were selected for the current systematic review and meta-
analysis. 10 research used temporary middle cerebral 
artery occlusion (tMCAO) to induce cerebral ischemia. 
Two of  these investigations used intraluminal blockage 
of  the middle cerebral artery, seven used bilateral carotid 
artery occlusion (BCAO), and one used endothelin-1 
microinjection. Permanent MCAO was found in 2 studies: 
photothrombosis induced by rose Bengal dye (1 study) 
and MCAO (1 study). Among 21 antagonist interventions, 
12 mGluR5 antagonist (MPEP = 9 and MTEP = 3) and 
5 mGluR1 antagonist (2 interventions of  LY367385 
and 3 interventions of  EMQMCM) were recorded. 
One intervention was treated with combined therapy of  
MPEP+LY367385, and 3 treatments were carried out 
with group I (mGluR1 and mGluR5) selective antagonist 
with MCPG, CBPG, and AIDA, respectively. The other 5 
agonist interventions were treated with mGluR5-specific 
agonist, CHPG (4 interventions) and group I selective 
agonist, DHPG (1 intervention). Furthermore, 10 out of  
26 interventions used Gerbils, 7 interventions used SD 
Rat, 6 interventions used Wister Rat, and 3 interventions 
used C57BL/6J mice in the experiments. Regarding the 
route of  administration, 11 interventions of  5 studies 
were performed via intracerebroventricular (i.c.v.) 

microinjection (stereotactic), 11 interventions of  another 
5 studies were delivered by intraperitoneal injection (ip), 
3 interventions of  one study were applied through the 
tail vein, and one intervention of  one study used the 
intrathecal route. Anesthetic agents were used in all 26 
interventions of  12 studies during stroke induction (Table 
2). The present study found 41 treatment groups, of  
which functional outcome was reported in 16 treatment 
groups (8 for Neurobehavioral, 4 for NMDA receptor, 
and 4 for brain temperature) of  8 studies, and structural 
outcome in 25 treatment groups (12 for infract volume, 
8 for neuroprotection and 5 for neuron loss) of  all 12 
articles (Table 3).
Interpretation of  quality score and risk of  bias assessment
The interquartile range for the Quality Score checklist 
items was 3–6, with a median score of  4 out of  10. 
Peer-reviewed journals have published all of  the studies. 
All studies avoided using anesthetics with known 
marked intrinsic neuroprotective properties; none used 
animals with relevant comorbidities (e.g., hypertension); 
none reported a sample size calculation or allocation 
concealment during the experiment; 11 studies reported 
compliance with animal welfare regulations; one study 
reported possible conflicts of  interest; and two of  twelve 
studies reported blinded assessment of  the results and 
randomized allocation to treatment groups (Table 4). The 
mean effect size in the current meta-analysis remained 
slightly high (-0.75 SMD with P > 0.05 for neurological 



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score, -1.37 SMD with P < 0.00001 for infract volume, 
1.73 SMD with P < 0.00001 for neuroprotection, and -1.35 
SMD with P < 0.00001 for neuron loss), even though the 
overall estimation of  the included outcomes represented 
larger effect sizes even after adjusting these effect sizes by 
subgroup and sensitivity analysis. Conversely, the effect 
sizes were less for the NMDA receptor (done by almost 
identical authors) and brain temperature (performed by 
nearly identical authors), at -0.41 SMD and -0.05 SMD, 
respectively; however, both effect sizes were statistically 
insignificant (P > 0.05). According to this study, the risk 
of  bias was assessed using SYRCLE’s risk of  bias tool for 
animal studies (Hooijmans et al., 2014) (Table 5).

Meta-Analysis of  Effect Sizes
Neurological score decreased in a meta-analysis of  eight 
treatment arms of  four studies with 32 animals in control 

groups and 60 animals in treatment groups of  both 
agonist and antagonist interventions (Table 1). However, 
the heterogeneity test among these 4 studies showed that 
the neurological score significantly favors the treatment 
(Supplementary Fig. 1). The sensitivity analysis (removal 
of  effect size >3 SMD) improved the reduction of  the 
neurological score effect size (Table 1) and heterogeneity, 
which significantly favors the treatment again. We did not 
compare the effectiveness of  various training regimens 
for this outcome because there aren’t many studies that 
evaluate neurobehavioral scores. The effect size increased 
by -2.07 SMD with 95% CI (-3.35, -0.79) after stratification 
by agonist or antagonist intervention; heterogeneity: 
Tau2 = 1.27; Chi2 = 12.42, df  = 3; I2 = 76%, overall P 
= 0.002; (Figure 2) in antagonist treatment arms, and it 
significantly (P < 0.05) affects the treatment. In this case, 
one intervention’s effect size was greater than three SMD.

Table 1: Effect sizes of  different outcomes measures
Measures Before adjustment After adjustment ES 

>3 
arms 
No.

Mean 
(ES)

95% CI No. P value Mean 
(ES)

95% CI No. P value

Neurological score* -0.23 -0.84, 0.39 4 0.47 -0.00 -0.57, 
0.56

3 0.99 -

Infarct volume* -0.94 -1.45, 
-0.43

5 0.0003 -0.82 -1.35,
 -0.28

4 0.003 -

Neurological 
score#

-2.07 -3.35, 
-0.79

4 0.002 -1.42 -2.17,
-0.67

3 0.0002 1

Infarct volume# -1.85 -2.52, 
-1.18

7 <0.00001 -1.63 -2.21,
-1.05

6 <0.00001 1

Neuroprotection# 2.48 1.50, 3.47 8 <0.00001 1.73 1.08, 
2.38

6 <0.00001 2

Neuron loss# -1.58 -2.18, 
-0.99

5 <0.00001 -1.35 -1.85, 
-0.85

4 <0.00001 1

Brain temperature# -0.34 -1.43, 0.75 4 0.54 -0.05 -0.62, 
0.52

3 0.87 1

NMDA receptor# -1.11 -2.45, 0.22 4 0.10 -0.41 -1.58, 
0.76

2 0.49 2

Neurological 
score##

-1.09 -1.94, 
-0.24

8 0.01 -0.75 -1.39, 
-0.11

7 0.02 1

Infarct volume## -1.52 -2.00, 
-1.04

12 <0.00001 -1.37 -1.79, 
-0.95

11 <0.00001 1

Note: For each effect size, the 95 % CI does not cross zero, and the p value <0.05 indicates that results favor mGluRs treatments, whereas 
the P value >0.05 does not favor mGluRs treatments. ES, Effect Size; CI, Confidence Interval; No, Number of  intervention. *Agonist 
interventions, #Antagonist Interventions, ##Agonist and antagonist interventions together.

Following antagonist treatment, the neurological 
score significantly decreased (P <0.05) according to 
sensitivity analysis adjustment of  effect sizes (Table 1). 
Additionally, we assessed the neurobehavioral outcomes 
that were most commonly observed in the mice, as 
well as the effect size of  group I mGluRs agonist and 
antagonist therapy, independently. The neurological 
score outcome for agonist-treated interventions was 

found to be lower than that of  antagonist-treated 
interventions in terms of  both effect magnitude and 
heterogeneity (Figure 2). The heterogeneity and effect 
size of  the included studies decreased even after 
sensitivity analysis (removal of  height effect size); but, 
surprisingly, the outcome did not significantly (P > 
0.05) favor the therapy before and after correction of  
interventions. 



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With 105 animals in the experimental groups and 46 in the 
control groups, the mean infarct size of  5 studies and 12 
interventions (both agonist and antagonist) was decreased 
(Figure 2). Although there were 12 treatment arms where 
effect size of  one treatment was >3.0, and after removal 
of  this inadaptable treatment, the heterogeneity of  
remaining interventions went down and the effect size 
was recorded (Table 1). Heterogeneity was Tau2 = 0.49; 
Chi2 = 15.94, df  = 6; I2 = 62%, overall P < 0.00001, 
and the mean infarct size in 7 antagonist interventions 
of  3 studies, which included 34 animals in control and 
70 animals in experimental groups, was -1.85 SMD 

with 95% CI (-2.52, -1.18) (Figure 3A). However, there 
was 1 intervention dominated by effect size 3.78. After 
removing this inadaptable treatment under sensitivity 
analysis, the heterogeneity was low and the effect size 
was -1.63 SMD with 95 % CI (-2.21, -1.05) (Table 1). 
Contrarily in 5 agonist interventions of  3 studies, the 
heterogeneity was I2 = 0 %; P = 0.0003 and infract size 
was -0.94 SMD (95 % CI, -1.45, –0.43) with < 1 SMD 
effect size in almost all interventions (excluding effect 
size -2.42 SMD) (Figure 3B). Removal of  this biggest 
inadaptable result in sensitivity analysis showed the effect 
size, -0.82 SMD with 95 % CI (-1.35, -0.28).

Figure 2: Neurobehavioral Effect size of  group I mGluRs across studies. The forest plot showed median effect size 
and 95% CI for the neurological score of  antagonist interventions (A) and agonist interventions (B) compared with 
the control group. Std, standardized; IV, inverse variance; CI, confidence interval; df, degrees of  freedom.

Figure 3: Infarct volume effect size of  group I mGluRs across studies. Forest plot showed median effect size and 
95% CI for infarct volume of  antagonist interventions (A) and agonist interventions (B) compared with the control 
group. Std, standardized; IV, inverse variance; CI, confidence interval; df, degrees of  freedom.



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The mean effect size for the neuroprotection or live 
neuron cells count included 5 studies and 8 antagonist 
interventions was measured as 2.48 SMD with 95 % CI 
(1.50, 3.47) where 2 interventions were more than 3 SMD, 
with the greatest SMD 5.65 in one study. The number 
of  animals (Wister Rat, Gerbils) in both control and 
experimental groups was 11. Heterogeneity was recorded 
as Tau2 = 1.41; Chi2 = 24.74, df  = 7; I2 = 72 %, overall 
P < 0.00001 (Figure 4). After removal of  inadaptable 
intervention (effect size > 3 SMD) in sensitivity analysis, 
the heterogeneity was found lower to Tau2 = 0.15; Chi2 = 
6.39, df  = 5; I2 = 22 %, overall P < 0.00001 and effect 

size was 1.73 SMD with 95 % CI (1.08, 2.38) (Table 1). 
Separately two antagonist interventions in Wister rat 
showed effect size > 2 SMD but the heterogeneity Tau2 

= 0.00; Chi2 = 0.02, df  = 1; I2 = 0 %, overall P < 0.0001 
(Supplementary Fig. 3A) whereas in 6 interventions of  
Gerbils showed effect size 2.50 SMD (>2 SMD in 3 
interventions with higher SMD 5.65) and heterogeneity 
was Tau2 = 1.95; Chi2 = 24.29, df  = 5; I2 = 79 %, overall 
P = 0.0001 (Supplementary Fig. 3B). After sensitivity 
analysis the effect size was found as 1.97 SMD with 95 % 
CI (0.96, 2.98) (Table 1).

Figure 4: Neuroprotection effect size of  group I mGluRs antagonist interventions across studies. The forest plot 
showed the median effect size and 95% CI for neuroprotection of  antagonist interventions compared with the control 
group. Std, standardized; IV, inverse variance; CI, confidence interval; df, degrees of  freedom

Figure 5: Effect size of  group I mGluRs antagonist interventions across studies. Forest plot showed median effect 
size and 95% CI for neuronal loss (A), brain temperature (B), and effect on NMDA receptor (C) compared with the 
control group. Std, standardized; IV, inverse variance; CI, confidence interval; df, degrees of  freedom.



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The size of  the effect of  antagonist treated neuron loss (5 
interventions of  3 studies included 29 animal in control 
and 49 in experimental groups) and brain temperature 
(4 interventions of  2 studies included 14 animal in 
control and 28 in experimental groups) outcomes were 
reduced by -1.58 SMD with 95 % CI (-2.18, -0.99) and 
-0.34 SMD with 95 % CI (-1.43, 0.75) respectively. The 
heterogeneity was measured in neuron loss outcome 
where in 4 interventions SMD were >1 with greater 
SMD 3.09 (Figure 5A). The heterogeneity with overall P 
= 0.54 was found in brain temperature outcome where 
3 interventions SMD were less than 1 and in one study 
SMD was -4.81 (Figure 5B). After sensitivity analysis the 
heterogeneity was same in both studies but overall P < 
0.00001 in neuronal loss and overall P = 0.87 in brain 
temperature outcomes and effect sizes were -1.35 SMD 
with 95 % CI (-1.85, -0.85) in neuronal loss and -0.05 
SMD with 95 % CI (-0.62, 0.52) in brain temperature 
outcomes (Table 1). The effect size for NMDA receptor 
of  4 antagonist interventions of  2 studies was found 
to be -1.11 SMD with 95 % CI (-2.45, 0.22). Here we 
found the effect size < 0.5 SMD in 2 interventions and 
> 3 SMD in another 2 interventions and heterogeneity 
with overall P = 0.10 (Figure 5C). After adjustment of  
effect size by sensitivity analysis (removal of  effect size 
> 3 SMD) the heterogeneity I2 = 0 %, and effect size 
was -0.41 SMD with 95 % CI (-1.58, 0.76) but it was 
statistically insignificant (P > 0.05) (Table 1).

Discussion
One of  the world’s major causes of  death and disability, 
ischemic stroke has been the focus of  intense research 
in recent years (Ström et al., 2013). Enhancing this 
endogenous process could be a treatment approach to 
improve functional outcome because adult neurogenesis 
is a restricted process in humans (Greenberg et al., 2007). 
In this regard, mGluR agonists and/or antagonists may be 
a good option to provide their protective function in the 
treatment of  stroke. Consequently, several writers have 
presented conflicting findings regarding the assessment 
of  deficits following experimental ischemia, depending on 
the species, strain, age, and experimental model employed, 
as well as the timing of  the test (Rosell et al., 2013). Several 
outcomes, including infarct volume of  agonist and 
antagonist interventions and neuroprotection, neuronal 
loss, and neurological score of  antagonist intervention, 
significantly favor the treatments, according to this meta-
analysis, which primarily looked at preclinical studies of  
group I mGluRs agonist and antagonist in the treatment 
of  animal ischemic stroke. Nevertheless, no correlation 
was found between the agonist or antagonist dosage and 
the delivery method, possibly because the majority of  
studies used intraperitoneal or intracerebroventricular 
stereotactic injections to deliver the drug to the lesion. 
However, our findings point to the need for additional 
molecular research on group I mGluRs agonists and 
antagonists for the treatment of  ischemic stroke in the 
future. The current study’s median quality score, using 
the same items from the Quality Score checklist, was 

4 (interquartile range: 3–6), which is lower than the 
preclinical studies on NSCs for ischemic stroke (Chen et 
al., 2016) and preclinical mesenchymal stromal cells for 
ischemic stroke (Vu et al., 2014). It is also consistent with 
the study on preclinical stem cell therapy (Lees et al., 2012). 
Lower quality studies typically exaggerate intervention or 
experimental effects (Schulz et al., 1995), while higher 
quality studies typically provide more effective evaluation 
of  preclinical research impacts (O’Collins et al., 2006). 
In this current meta-analysis, moderate effect sizes were 
observed. For group I mGluRs agonists, the effect sizes 
for two outcomes, neurological score and infarct volume, 
were identified. The heterogeneity in neurological scores 
was lower but not statistically significant (P > 0.05). This 
meta-analysis reveals that neurological scores significantly 
favor treatment with group I mGluRs antagonists and 
disfavor agonist treatment, aligning with previous studies 
(Chen et al. 2016). Differences in drug dose, administration 
route, type of  ischemic stroke, and animal models may 
contribute to the variations in effect sizes within the 
agonist or antagonist groups, or between them. The intra-
cerebroventricular (icv) route was used by 11 interventions 
across 5 studies (Riek-Burchardt et al., 2007; Bao et al., 
2001; Norio et al., 2012; Norio et al., 2010; Bruno et al., 
1999), and the intraperitoneal (ip) route was used by 11 
interventions across 5 studies (Kinga et al., 2007; Dorota 
et al., 2006; Elena et al., 2002; Muralikrishna et al., 2000; 
Malgorzata et al., 2006). Overall, the assessment indicates 
that the icv route of  administration is more effective than 
ip injection. Due to these factors, significant heterogeneity 
existed in behavioral and anatomical outcomes, which we 
addressed through subgroup and sensitivity analyses, as 
well as bias risk assessments. 
Generally, an effect size >0.8 is considered as a large effect 
(Schulz et al. 1995). In this meta-analysis considerable 
lower effect sizes were found in the neurological score 
against agonist interventions and brain temperature 
outcome against antagonist interventions, but neither of  
the outcomes were not statistically significant (P >0.05). 
After removing the inadaptable treatment with effect sizes 
>3 from a particular treatment group, the rest effect sizes 
were improved significantly in some cases, but it remained 
high effect sizes in infract volume, neurological score, 
neuroprotection, neuron loss, and effects on NMDA 
receptors in antagonist interventions. For neurological 
score and infarct volume, the biggest effect sizes were 
-4.57 SMD and -3.78 SMD, respectively (Kinga et al. 
2007), but these effect sizes were lower than the study 
on transplantation of  NSCs modified by glial cell line-
derived neurotrophic factor (GDNF) gene to native NSCs 
transplantation after ischemic stroke (Chen et al. 2009). 
The primary weakness of  this investigation was that it 
was observational rather than experimental. Only the 
association of  studies was provided; all other findings are 
hypotheses. Even if  our search was thorough, there’s a 
chance that some published research was overlooked. The 
current analysis may overestimate the effects of  group I 
mGluRs agonist and antagonist treatments in ischemic 
stroke due to the potential use of  low-quality research. 



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Conversely, there were some signs of  publication bias 
influencing the meta-analysis’s findings (Feng et al., 2016), 
a typical occurrence that often affects animal study meta-
analyses (Briel et al., 2013; Korevaar et al., 2011). We were 
unable to compare our data with any meta-analyses on 
ischemic stroke and mGluRs. The use of  mGluRs in 
experimental ischemic stroke, however, may have been 
reviewed by our work, which is likely to have documented 
the primary trend in the field of  mGluRs treatment. 

CONCLUSION
In preclinical ischemic animal models, group I mGluRs 
antagonists were primarily linked to significantly better 
functional and structural outcomes, according to the 
current systematic review and meta-analysis. It also 
offered some helpful tools for future therapeutic research 
on mGluRs in clinical ischemic stroke. Long-term 
consequences, risk assessment, and improvements in 
neural structural and functional regeneration and repair 
should all be taken into account in future research, 
including mGluRs treatment. 

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