1. Medicine
  2. Neuroscience

Preclinical systematic review of CCR5 antagonists as cerebroprotective and stroke recovery enhancing agents

  1. Ayni Sharif
  2. Matthew S Jeffers
  3. Dean A Fergusson
  4. Raj Bapuji
  5. Stuart G Nicholls
  6. John Humphrey
  7. Warren Johnston
  8. Ed Mitchell
  9. Mary-Ann Speirs
  10. Laura Stronghill
  11. Michele Vuckovic
  12. Susan Wulf
  13. Risa Shorr
  14. Dar Dowlatshahi
  15. Dale Corbett
  16. Manoj M Lalu  Is a corresponding author
  1. Clinical Epidemiology Program, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Canada
  2. School of Epidemiology and Public Health, University of Ottawa, Canada
  3. Department of Medicine, University of Ottawa, Canada
  4. Office for Patient Engagement in Research Activity (OPERA), Ottawa Hospital Research Institute, Canada
  5. Patient Partner, Blueprint Translational Research Group, Ottawa Hospital Research Institute, Canada
  6. Ottawa Hospital Library Services, The Ottawa Hospital, Canada
  7. Division of Neurology, Department of Medicine, The Ottawa Hospital, Canada
  8. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Canada
  9. Department of Anaesthesiology and Pain Medicine, The Ottawa Hospital, Canada
https://doi.org/10.7554/eLife.103245.3
Share this article
Cite this article
  1. Ayni Sharif
  2. Matthew S Jeffers
  3. Dean A Fergusson
  4. Raj Bapuji
  5. Stuart G Nicholls
  6. John Humphrey
  7. Warren Johnston
  8. Ed Mitchell
  9. Mary-Ann Speirs
  10. Laura Stronghill
  11. Michele Vuckovic
  12. Susan Wulf
  13. Risa Shorr
  14. Dar Dowlatshahi
  15. Dale Corbett
  16. Manoj M Lalu
(2025)
Preclinical systematic review of CCR5 antagonists as cerebroprotective and stroke recovery enhancing agents
eLife 14:RP103245.
https://doi.org/10.7554/eLife.103245.3
  2. Download BibTeX
  3. Download .RIS
5 figures, 7 tables and 3 additional files

Figures

Figure 1
Download asset Open asset
Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram.
Figure 2 with 4 supplements
Download asset Open asset
C-C chemokine receptor type 5 (CCR5) antagonists reduce infarct volume.

Data is presented as a forest plot with standardized mean differences and 95% confidence intervals. Effect sizes <0 favours drug treatment and >0 favours control. Data is stratified by timing of CCR5 antagonist administration (pre- or post-stroke induction). The ‘RE Model for All Studies’ represents a pooled estimate of the CCR5 antagonist drug effect on infarct volume from all studies combined. Separate pooled estimates are also reported for post- and pre-stroke CCR5.

Figure 2—figure supplement 1
Download asset Open asset
Sensitivity analysis for all included studies that reported infarct volume on a percentage scale.

Overall, both the original analysis using standardized mean differences (Figure 2) and the sensitivity analysis demonstrate a significant cerebroprotective effect of C-C chemokine receptor type 5 (CCR5) antagonists. Data is presented as a forest plot with mean differences and 95% confidence intervals. Effect sizes <0 favours CCR5 antagonist treatment and >0 favours control. Data is stratified by timing of CCR5 antagonist administration (pre- or post-stroke induction). The ‘RE Model for All Studies’ represents a pooled estimate of the CCR5 antagonist drug effect on infarct volume from all studies combined. Separate pooled estimates are also reported for post- and pre-stroke CCR5. T (n) = number of animals in the CCR5 treatment group. C (n) = number of animals in the control group.

Figure 2—figure supplement 2
Download asset Open asset
Subgroup analysis for all included studies of pre- and post-stroke C-C chemokine receptor type 5 (CCR5) antagonist administration that reported infarct volume.

Each row represents pooled estimate data from studies within that subgroup. Data is presented as a forest plot with a standardized mean difference and 95% confidence intervals. The I2 value represents the statistical heterogeneity within each subgroup. Effect sizes <0 favours drug treatment and >0 favours control. The ‘RE Model for All Studies’ represents a pooled estimate of the CCR5 antagonist drug effect on infarct volume from all studies combined. Considering all six experiments (irrespective of administration timing of CCR5 antagonist), subgroup analysis demonstrated no difference in effect size when considering route of administration, stroke model, species type, drug, dose, or whether behaviour tests were assessed.

Figure 2—figure supplement 3
Download asset Open asset
Subgroup analysis for all included studies of post-stroke drug administration of a C-C chemokine receptor type 5 (CCR5) antagonist that reported infarct volume.

Each row represents pooled estimate data from studies within that subgroup. Data is presented as a forest plot with a standardized mean difference and 95% confidence intervals. The I2 value represents the statistical heterogeneity within each subgroup. Effect sizes <0 favours drug treatment and >0 favours control. The ‘RE Model for All Studies’ represents a pooled estimate of the CCR5 antagonist drug effect on infarct volume from all post-stroke drug administration of a CCR5 antagonist studies combined. Subgroup analysis considering only studies that administered CCR5 antagonists post-stroke induction demonstrated no difference in effect size when considering any of the subgroups.

Figure 2—figure supplement 4
Download asset Open asset
Subgroup analysis for all included studies of pre-stroke drug administration of a C-C chemokine receptor type 5 (CCR5) antagonist that reported infarct volume.

Each row represents pooled estimate data from studies within that subgroup. Data is presented as a forest plot with a standardized mean difference and 95% confidence intervals. The I2 value represents the statistical heterogeneity within each subgroup. Effect sizes <0 favours drug treatment and >0 favours control. The ‘RE Model for All Studies’ represents a pooled estimate of the CCR5 antagonist drug effect on infarct volume from all pre-stroke drug administration of a CCR5 antagonist studies combined. Subgroup analysis of studies that administered CCR5 pre-stroke induction suggested that infarct volume was reduced to a greater extent by the intraluminal suture stroke model versus other models (p = 0.04), in rats versus mice (p = 0.01), with DAPTA versus TAK-779 (p = 0.01), and when behaviour tests were performed versus not (p = 0.01).

Figure 3
Download asset Open asset
Synthesis without meta-analysis for all included preclinical C-C chemokine receptor type 5 (CCR5) antagonist studies that reported motor and/or cognitive behavioural outcomes.

Data is presented as a forest plot with a standardized mean difference and 95% confidence intervals. Effect sizes <0 favours drug treatment and >0 favours control.

Figure 4
Download asset Open asset
Modified risk of bias traffic light plot in accordance with the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool.

Yellow represents an unclear risk of bias, green represents a low risk of bias, and red represents a high risk of bias. Blue represents some concerns of a risk of bias. The risk of bias was ‘unclear’ across all studies for the domains of baseline characteristics because of missing data in the studies, random housing because no details on this domain were reported, and random outcome assessment because no details of how cohorts of animals were selected to perform certain outcomes nor how the order of outcome assessment proceeded. Four studies did not report on allocation concealment, and two studies did not report on blinding investigators and outcome assessors and were deemed as having an ‘unclear’ risk of bias. 80% of studies exhibited a ‘high’ risk for incomplete outcome data. Similarly, three studies (60%) had a ‘high’ risk of selective outcome reporting since all expected outcomes discussed in the methods of the articles did not align with their results. Other potential sources of bias considered included the source of funding (industry funded), contamination of pooling drugs (additional treatment which might influence or bias the result), unit error analysis (all animals receiving the same intervention are caged together, but analysis was conducted as if every single animal was one experimental unit), design-specific risks of bias (reporting details of which animals performed the same or different outcomes), and the addition of new animals to replace dropouts from the original population. Two studies (40%) had a ‘high’ risk in at least one of these additional categories.

Appendix 1—figure 1
Download asset Open asset
Potential mechanistic pathways and proposed domains of biological activity underlying CCR5 antagonist’s cerebroprotective and neural repair effects post-stroke described in the included studies.

A list of mechanistic evidence supporting these pathways was extracted from included studies in Appendix 1—table 1. This figure was created using BioRender.com.

Tables

Table 1
Summary of study and animal model characteristics of included articles.
AuthorYearCountrySpeciesStrainStroke typeStroke modelSexWeightAge
Li et al., 20162016ChinaRatWistarIschaemicIntraluminal sutureMale260–300 gN/A
Takami et al., 20022002JapanMiceddYIschaemicIntraluminal sutureMaleN/A4 weeks
Chen et al., 20222022ChinaMiceC57/BL6IschaemicPermanent middle cerebral artery occlusionMale25–30 g8–10 weeks
Yan et al., 20212021ChinaMiceCD1HaemorrhagicIntracerebral haemorrhagicMale30–40 gN/A
Joy et al., 20192019USAMiceC57/BL6IschaemicPhotothromboticMale25–30 g8–20 weeks
Table 2
Summary of intervention characteristics.
AuthorDrugDose (mg/kg)RouteTimingDoses(total #)Outcomes measured(treatment n/control n)Outcome window(post-stroke)
Li et al., 2016DAPTA (D-Ala-Peptide T-Amide)0.01SC15-min pre-stroke1

  •   Infarct volume (5/5)

  •   Neurological deficit score (5/5)

24 hr
Takami et al., 2002TAK-7795ICV10-min pre-stroke1

  •  Infarct volume (10/6)

48 hr
50ICV10-min pre-stroke

  •  Infarct volume (13/6)

0.25IV50-min post-stroke

  •  Infarct volume (17/18)

Chen et al., 2022Maraviroc20IP1.5-, 24-, and 48-hr post-stroke3

  •    Infarct volume (5/5)

  •    Longa score (5/5)

  •    Neurological deficit score (5/5)

72 hr
Yan et al., 2021Maraviroc0.15IN1-hr post-stroke1

  •    Garcia test (6/6)

  •    Limb placement (6/6)

  •    Corner turn test (6/6)

72 hr

  •   Foot fault (8/8)

  •   Rotarod (8/8)

3 weeks

  •  Probe quadrant duration (8/8)

25 days
24-hr post-stroke

  •    Garcia test (6/6)

  •    Limb placement (6/6)

  •    Corner turn test (6/6)

72 hr
Joy et al., 2019Maraviroc100IP24-hr post-stroke through daily injections for 9 weeks63

  •  Infarct volume (5/5)

9 weeks

  •   Grid walk (10/10)

  •   Forelimb (10/10)

8 weeks
24-hr post-stroke then daily for 3 weeks21

  •   Grid walk (10/10)

  •   Cylinder test (9/8)

9 weeks
3–4 weeks post-stroke then daily for 11 weeks56

  •   Grid walk (9/9)

  •   Cylinder test (9/9)

11 weeks

  1. ICV = intracerebroventricular; IN = intranasal; IP = intraperitoneal; IV = intravenous; SC = subcutaneous.

Table 3
Alignment of included preclinical studies with STAIR recommendations and CAMAROS trial parameters.
RecommendationOverall preclinical evidenceCAMAROS trial alignmentNotes
Candidate treatment qualification
Establish treatment dose–responseYesNo

  • Preclinical – doses across all studies from 0.01 to 100 mg/kg

  • Six doses tested for infarct volume, three doses for behavioural effects

  • Joy et al. demonstrated that 100 mg/kg of maraviroc in mice results in cerebrospinal fluid levels lower than in humans (13.8 ± 5.4 vs. 33.6–60 ng/ml)

  • CAMAROS – participants take 300 mg doses twice daily for 8 weeks

  • Interpretation – maximum preclinical dose may not represent clinical levels

Treatment given after clinically relevant delayed times (1- to 4.5-hr post-stroke)YesYes

  • Preclinical – 3/5 studies (all maraviroc) administered drug from 1 to 24 hr post-stroke (acute phase)

  • Joy et al. initiated maraviroc administration at 20 days post-stroke for 11 weeks (subacute phase)

  • CAMAROS – participants recruited between 5 days and 6 weeks post-stroke (acute/early subacute)

  • Interpretation – one experiment in a time window relevant to clinical trial

Both histologic and behavioural outcomes at acute (1–3 days) and chronic (7–30 days) time pointsYesYes

  • Preclinical – 2/5 studies included both histologic and behavioural outcomes

  • Mainly tasks of spontaneous movement (e.g., cylinder) or motor coordination (e.g., grid walk)

  • Tests ranged from 3 days (acute) to 11 weeks (chronic) post-stroke for all included studies, but short-term assessment may only delay cell death (Corbett and Nurse, 1998)

  • CAMAROS – motor learning (Fugl-Meyer Upper Extremity Assessment Score and 10-Meter Walk Test Score) measured as the primary outcome at baseline, 4 week (late subacute), 8 week (late subacute), and 6 month (chronic)

  • Interpretation – challenging to directly compare preclinical and clinical motor tasks, but testing range is comparable. Most relevant Joy et al. experiment (subacute administration) did not measure histologic outcomes

Treatment reaches presumed target and causes expected physiological effects that can be assessed with a clinically relevant biomarkerYesNA

  • Preclinical – 5/5 studies demonstrated trends for CCR5 antagonism to reduce infarct volume. Plausible that CCR5 influences stroke-relevant mechanisms

  • CAMAROS – does not include outcomes to assess treatment mechanisms

Treatment able to pass the blood–brain barrierYesNA

  • Preclinical – 1/5 studies used mass spectrometry to demonstrate that maraviroc is present in the brain and cerebrospinal fluid

  • CAMAROS – does not include outcomes to assess presence of drug in the brain

Preclinical assessment/validation
Aging/adult ageNoNo

  • Preclinical – 4/5 studies used rodents with weights/ages consistent with young adulthood; 0/5 studies used rodents ≥10 months old.

  • CAMAROS – age ≥18 year old adult participants eligible for recruitment

  • Interpretation – preclinical studies consistent with CAMAROS eligibility criteria; however, no preclinical study examined middle-aged or elderly animals that would be more representative of the trial and overall stroke populations

Male and female animalsNoNo

  • Preclinical – 0/5 studies included female animals

  • CAMAROS – both male and female sexes eligible for recruitment

  • Interpretation – effects of CCR5 antagonists for stroke recovery in female animals represents a critical knowledge gap

Animals with comorbiditiesNoNo

  • Preclinical – 0/5 studies included animals with common stroke comorbidities (e.g., diabetes, hypertension, etc.)

  • CAMAROS – participants with stroke comorbidities eligible for recruitment

  • Interpretation – effects of CCR5 antagonists for stroke recovery in animals with common stroke comorbidities represents a critical knowledge gap

Evidence from two or more laboratoriesYesNo

  • Preclinical – 5/5 studies demonstrated stroke-related benefits; however, no study had their results replicated by independent laboratories

  • CAMAROS – trial protocol will be replicated by multiple study sites

  • Interpretation – future preclinical experiments could consider assessing effects using a multilaboratory approach, or independently replicate the effects of existing preclinical studies

Gyrencephalic speciesNoNo

  • Preclinical – 5/5 studies conducted in lissencephalic (rodent) species.

  • CAMAROS – human participants

  • Interpretation – effects of CCR5 antagonists for stroke recovery in gyrencephalic species represents a critical knowledge gap

Tests during the awake phase of animalsNoNo

  • Preclinical – 0/5 studies reported assessing outcomes at night (i.e., awake phase of rodents)

  • CAMAROS – follow-up occurs during daytime hours (i.e., awake phase of humans)

  • Interpretation – future preclinical studies should conduct behavioural testing during the awake phase to better align with human testing conditions

Table 4
Alignment of included preclinical studies with additional STAIR/SRRR items and CAMAROS trial parameters.
RecommendationPreclinical evidenceCAMAROS alignmentNotes
Testing in both permanent and transient occlusion modelsYesYes

  • Preclinical – 2/5 studies permanent occlusion, 2/5 transient occlusion, 1/5 haemorrhagic

  • CAMAROS – participants with ischaemic anterior circulation stroke, with or without reperfusion treatments eligible for enrollment

Monitoring of treatment effects on physiological parameters, including temperature, both during and after ischaemiaNoNA

  • Preclinical – 1/5 studies (Takami et al., 2002; TAK-779) monitored and provided data on temperature for an extended period post-stroke

  • CAMAROS – participants will not be administered maraviroc in a cerebroprotective context

Testing interaction with thrombolytics and other medications commonly administered in acute strokeNoNo

  • Preclinical – 0/5 studies included assessed drug interactions

  • CAMAROS – participants may or may not be exposed to thrombolytics or other concomitant medications that could interact with recovery-inducing effects of maraviroc

Animal model should produce infarction similar in relative size and location to that observed in humansYesYes

  • Preclinical – 1/5 studies (Joy et al., 2019; maraviroc) produced infarcts in motor regions of control animals that were less than 25% of hemispheric volume

  • CAMAROS – participants with ischaemic anterior circulation stroke with hemiparesis requiring rehabilitation eligible for enrollment

For studies claiming recovery effects, analysis of infarct volume should be performed to show equivalency of injury in the treated and stroke control groupsNoNA

  • Preclinical – 0/1 experiments in late subacute/early chronic post-stroke phase (Joy et al., 2019) demonstrated that each treatment group had equivalent baseline stroke volumes. This could potentially confound observed behavioural effects

For studies claiming recovery effects, tissue repair/neuroplasticity processes should be quantified and directly related to behavioural recoveryYesNA

  • Preclinical – 1/5 studies (Joy et al., 2019) demonstrated maraviroc association with dendritic spine preservation, axonal projections to contralateral cortex, reduced inflammatory response, and upregulation of CREB/DLK signalling

  • CAMAROS – outcomes to assess mechanism of recovery are not included

For studies claiming recovery effects, initial impairment with spontaneous recovery that plateaus significantly below pre-stroke performanceNoNA

  • Preclinical – 1/5 studies assessed long-term outcomes (Joy et al., 2019). Large variability in initial levels of impairment across experiments. Control animals demonstrate limited spontaneous recovery or atypical worsening of performance across time in multiple experiments.

  • CAMAROS – placebo participants will receive 8-week exercise program making assessment of spontaneous recovery difficult

Behavioural effects should be assessed across a battery of domains, including both skilled and spontaneous upper limb and hindlimb useNoNo

  • Preclinical – 2/5 studies included battery of behavioural tasks, but no study assessed effects on upper extremity skilled reaching/grasping or alteration of movement kinematics

  • CAMAROS – two primary outcomes: (1) upper extremity assessment using Fugl-Meyer; (2) change in 10-meter walk test score. Preclinical outcomes have limited relevance to Fugl-Meyer

Mechanism of action should be assessed through gain of function/loss of function studies and directly associated to behavioural effectsYesNA

  • Preclinical – 1/5 studies Joy et al., 2019 demonstrated that knockdown of DLK signalling using small hairpin DLK is able to block beneficial behavioural effects of CCR5 knockdown, providing a possible mechanism for stroke recovery-inducing effec

  • CAMAROS – outcomes to assess mechanism of recovery are not included

Testing interactions of treatment with clinically inspired best practice, such as training or enrichmentNoNo

  • Preclinical – 0/5 studies included behavioural therapy/rehabilitative interventions

  • CAMAROS – all participants (including placebo) will participate in an 8-week exercise program

Appendix 1—table 1
List of outcomes used to determine potential mechanisms of action, by study.
PaperMechanistic evidence presented
Takami et al., 2002 – TAK-779

  • Infarct volume reduction (reduced by TAK-779)

  • MPO + Mac-1-alpha antibody used to stain infiltrating neutrophils/macrophages/microglia (Mac-1-alpha reduced by TAK-779/MPO not decreased) – neutrophils the same, macrophages/microglia reduced

Li et al., 2016 – DAPTA

  • Cell death reduction (TUNEL/H&E)

  • Western blot – ROCK2/P-MLC2 reduced (by DAPTA)

Joy et al., 2019 – maraviroc

  • CCR5 knockdown FACS isolated neuronal assay -> CREB/pCREB/DLK significantly increased. Erk(p44), GAP43, SAP/JNK1+2 increased, but not significantly. P38 decreased, but not significantly

  • Two-photon imaging – CCR5 knockdown + maraviroc -> increased dendritic spine count, fewer lost

  • BDA axonal quantification – CCR5 knockdown + maraviroc -> increased bihemispheric sprouting

  • GFAP/IBA-1 immunostaining – CCR5 knockdown + maraviroc -> reduced immunoreactivity. Decreased Ly6C (neutrophil) and Ly6Clow (macrophage) recruitment

Yan et al., 2021 – maraviroc

  • Cell death reduction (TUNEL/FJC/cleaved caspase 1/Nissl)

  • Western blot – maraviroc -> increased PK A-Calpha/pCreb -> decreased NLRp1/cleaved caspase 1/IL-1B/apoptosis-associated speck protein/N-gasdermin D/IL-18

  • Western blot -> effects reversed by 666-15

  • Western blot -> rCCL5 shows reversed effects from maraviroc -> rCCL5 + cAMP reverses those effects

Chen et al., 2022 – maraviroc

  • Infarct volume/cell death reduction (TTC/TUNEL)

  • Western blot – maraviroc -> increased Bcl2:BAX ratio -> increased IκBα, ->decreased P-IκBα/P-P65/P-P38/P-JNK

  • Western blot – P-JNK decreased, Anisomycin reverses the effect on P-JNK

qRT-PCR, ELISA -> reduced IL-1B/IL-6/TNF-alpha
Appendix 2—table 1
Readiness of CCR5 antagonists for translation based on the PRIMED2 tool.
PRIMED2 domainTAK-779DAPTAMaravirocCCR5 antagonism (all agents)
Sex of animals
(0 – male OR female; 2 – both sexes)		0000
Age of animals
(0 – young only; 2 – older adults)		0000
Species and strains
(0 – one rodent species/strain;
1 – ≥2 rodent species/strains;
2 – rodents AND primates)		0011
Reproducibility
(0 – one species, one laboratory;
1 – ≥2 species, one lab OR ≥2 labs, one species;
2 – ≥2 species AND ≥2 labs)		0022
Treatment time epoch
(0 – no significant benefit;
1 – benefit in one epoch;
2 – benefit in ≥2 epochs)		1122
Baseline comorbidities
(0 – healthy animals only;
1 – one comorbid condition;
2 – ≥2 comorbid conditions)		0000
Feasible time window
(0 – treatment <45 min after ischemia onset;
2 – ≥45 min after ischemia onset)		0022
Dose–response
(0 – one dose;
2 – multiple doses with dose–response relationship)		0000
Feasible route of delivery
(0 – infeasible route [e.g., intraventricular injection];
1 – semi-infeasible route [e.g., intraarterial injection];
2 – feasible route [e.g., intravenous injection])		2112
Behavioural and/or long-term outcome assessment
(0 – no benefit;
1 – behavioural OR other outcome ≥30 days post-stroke;
2 – behavioural AND outcomes ≥30 days post-stroke)		0022
Typical infarct volume reduction magnitude
0 – small effect (Cohen’s d 0.2–0.39);
1 – medium effect (Cohen’s d 0.4–0.69);
2 – large effect (Cohen’s d≥0.7)		2222
Readiness for translation score
(0–7 – low; 8–15 – medium; 16–22 – high)		Low (5)Low (4)Medium (12)Medium (13)
Appendix 3—table 1
GRIPP2 short form checklist.
Section and topicItem
1: AimTo conduct a preclinical systematic review assessing the effects of C-C chemokine receptor type 5 (CCR5) antagonists on motor and cognitive impairment following stroke. To collaborate with a panel of patients and caregivers with lived experience of stroke throughout the development and conduct of the preclinical systematic review.
2: MethodsA panel of eight patients and caregivers with lived experience of stroke was recruited to join the research team through the Heart & Stroke Foundation and the Patient and Family Advocacy Program at The Ottawa Hospital. Recruitment advertisements were distributed to both organizations. The patients and caregivers were involved in developing the research question and the protocol (i.e., elements of the AMICO question presented in the Methods section); identifying data items for extraction; conduct of the review including screening and extraction; interpreting the review results; and contributed to edits to the final manuscript. Patients and caregivers attended monthly virtual meetings. These meetings provided background knowledge of preclinical stroke, systematic review conduct, and discussed research findings as the review progressed. Patients provided insights into their lived experiences with stroke and helped identify priority areas that they were interested in. Patients and caregivers were offered financial compensation and co-authorship in recognition of their contributions to the research project.
3: ResultsPatient engagement contributed to the study in several ways, including:

  • Informing the research question with the patient partner experience: patient partners have lived experience of stroke and provided patient priorities to analyze in our review

  • Refining our primary and secondary outcomes to include patient priorities

  • Developing of the protocol to include non-technical language

  • Editing screening and extraction forms

  • Participating as reviewers in abstract and full-text level screening

  • Participating as reviewers in extraction

  • Attending an international stroke conference and participating as co-authors of an abstract presented there

  • Interpretating analysed data, including identifying patient important barriers and limitations to incorporate in the discussion

4: DiscussionOverall, patient engagement was successful in informing review development and conduct. Additionally, the researchers on the team learned from the patient panel. The patient panel brought a unique perspective to the planning and conduct of a preclinical systematic review. Additionally, members of the panel stated that the experience was useful for them as they gained new insights into preclinical research.
5: ReflectionsEngagement was embedded within the research project from the inception to dissemination, where patient partners were members of the larger team. Patient partners directed us to outcomes for the systematic review that critical clinically to patients in the chronic phase of stroke recovery. Their participation in the conduct of the review facilitated meaningful collaborations and discussion.

Additional files

Supplementary file 1

Search strategy.

https://cdn.elifesciences.org/articles/103245/elife-103245-supp1-v1.zip
Supplementary file 2

Data extraction forms.

https://cdn.elifesciences.org/articles/103245/elife-103245-supp2-v1.zip
MDAR checklist
https://cdn.elifesciences.org/articles/103245/elife-103245-mdarchecklist1-v1.docx

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ayni Sharif
  2. Matthew S Jeffers
  3. Dean A Fergusson
  4. Raj Bapuji
  5. Stuart G Nicholls
  6. John Humphrey
  7. Warren Johnston
  8. Ed Mitchell
  9. Mary-Ann Speirs
  10. Laura Stronghill
  11. Michele Vuckovic
  12. Susan Wulf
  13. Risa Shorr
  14. Dar Dowlatshahi
  15. Dale Corbett
  16. Manoj M Lalu
(2025)
Preclinical systematic review of CCR5 antagonists as cerebroprotective and stroke recovery enhancing agents
eLife 14:RP103245.
https://doi.org/10.7554/eLife.103245.3