Main Research Findings

1) Administration of Cerebrolysin during the subacute stroke phase was found to enhance motor recovery and neuroplasticity through the corticospinal tract.

2) When Cerebrolysin was administered to patients during the subacute stroke phase there were significant improvements in functional motor recovery in paretic upper extremities.

 

Selected Data

1) The research team of Chang et al evaluated the ability of Cerebrolysin to enhance motor recovery in patients with moderate to severe motor impairments when administered in combination with standard rehabilitation. This study investigated the effects of Cerebrolysin on motor recovery and neuroplasticity in stroke patients. The trial was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted across multiple institutions.

Patients were included in the study if they had a first unilateral cortical, subcortical, or cortical-subcortical infarction confirmed by CT or MRI within seven days after stroke, with moderate to severe motor impairments measured using the Fugl-Meyer Assessment (FMA) scored 0-84), aged between 18 and 80, and had inpatient status. Exclusion criteria included unstable stroke, major neurological or psychiatric disorders, severe systemic diseases, substantial alertness reduction (NIHSS item 1a score ≥2), pregnancy, allergy to Cerebrolysin, participation in another stroke study, abnormal lab results, or prior exposure to porcine brain peptides. Informed consent was obtained from all participants, and the study was approved by institutional review boards [1].
Patients were screened within seven days post-stroke, with demographic, medical history, physical, and laboratory data collected. Eligible patients were randomized to receive either Cerebrolysin in doses of 30 mL in 100 mL saline delivered via IV infusion over 30 minutes or placebo administered 100 mL saline daily for 21 days, in combination with standardized rehabilitation that included 2 hours of physical therapy and 1 hour of occupational therapy on weekdays. Prior to enrollment, all patients completed passive range of motion exercises but no comprehensive rehabilitation. Motor function and safety were assessed at baseline (T0), post-treatment (T1), two months (T2), and three months (T3), after stroke onset. Neuroplasticity was evaluated using diffusion tensor imaging and resting-state functional MRI (rsfMRI) at T0, T1, and T3 [1].
Stroke severity at baseline was measured using the National Institutes of Health Stroke Scale (NIHSS), and lesion volumes were assessed through structural MRI. Lesion masks were created and analyzed in the Montreal Neurological Institute (MNI) space. Motor function was evaluated using FMA, which measures impairment severity with separate scores for the upper limb (FMA-UL), lower limb (FMA-LL), and total score (FMA-T). FMA has well-established reliability and validity across different stroke recovery phases.
Neuroplasticity assessment involved DTI and rsfMRI data obtained using a 3 Tesla MRI scanner. Diffusion tensor imaging was performed using a single-shot diffusion-weighted echo planar imaging sequence, acquiring 46 whole-brain images per patient, including 45 high-diffusion-weighted images and one non-diffusion-weighted image. Fractional anisotropy, axial diffusivity, and radial diffusivity were computed for each voxel and mapped onto the MNI space. To assess corticospinal tract integrity, a template CST from 23 healthy age-matched controls was used. Tract-wise diffusion tensor imaging parameters were computed as the average over the entire corticospinal tract rather than specific regions of interest. Fractional anisotropy, axial diffusivity, and radial diffusivity were computed for the ipsilesional hemisphere corticospinal tract [1].
rsfMRI data were collected using the same MRI scanner, with each patient undergoing 100 whole-brain image acquisitions via gradient echo planar imaging sequence. The images consisted of 35 axial slices with 4.00 mm thickness and 1.72 mm × 1.72 mm in-plane resolution. Preprocessing was performed using Statistical Parametric Mapping and the Data Processing Assistant for Resting-State fMRI. Preprocessing steps included spatial realignment, normalization to MNI space, spatial smoothing with a Gaussian kernel, systematic drift removal, regression of nuisance covariates, and band-pass filtering at a frequency of 0.01 to 0.08 Hz.
To estimate the sensorimotor network, the primary motor cortex in the ipsilesional hemisphere served as the reference for determining correlation coefficients with other brain regions. The sensorimotor network was displayed by thresholding statistical parametric maps derived from one-sample t-tests, with corrections for multiple comparisons. The lateralization index was computed between bilateral primary sensorimotor cortices based on correlation coefficient maps. Lateralization index values near zero indicated symmetrical functional connectivity, consistent with healthy individuals [1].
2) The research team of Mitrović et al assessed how administration of Cerebrolysin in combination with standard rehabilitation affects motor recovery and neuroplasticity in individuals in the acute stroke phase. The trial included 110 patients, both male and female, aged 18 and older, with neuro radiologically confirmed ischemic stroke and severe motor impairment scored as NIHSS >14. Eligible patients were admitted to the neurorehabilitation inpatient department between the seventh and fourteenth day after stroke onset [2].
Patients were included based on specific criteria: first-time ischemic stroke in the subacute phase (7–14 days post-stroke), cortical or subcortical stroke confirmed via imaging, severe upper limb paresis, the ability to sit unaided, and sufficient cognitive function (MMSE > 24) to comprehend instructions. Patients were excluded if they had previous strokes, bilateral paresis, psychiatric or neurological disorders, severe medical conditions that could interfere with treatment, prior use of brain peptides, allergies to Cerebrolysin, severe memory deficits.
Out of 112 patients assessed for eligibility, 60 met the criteria and were included in the study. The remaining 52 were excluded for the following reasons: 27 did not meet inclusion criteria, 13 had comorbidities preventing treatment participation, and 12 declined to enroll. All participants underwent comprehensive medical evaluations, including anamnesis, laboratory tests, and clinical assessments [2].
Randomization was performed using a computerized table of random numbers, with 60 sequentially numbered, opaque, sealed envelopes ensuring balanced group allocation. The statistician remained blinded to group assignments until the final analysis. Given the heterogeneity of previous studies regarding Cerebrolysin dosage and treatment duration, this study followed a protocol based on meta-analysis data and prior clinical trials. The intervention group received 30 mL of Cerebrolysin intravenously, diluted in 70 mL saline, over 30 minutes daily for 21 days. The placebo group received an equivalent volume of saline via intravenous infusion. Both groups underwent conventional inpatient rehabilitation for three weeks, followed by outpatient rehabilitation three times weekly until day 90 [2].
The rehabilitation program consisted of 45–60 minutes of physiotherapy and 45–60 minutes of occupational therapy per day. Physiotherapy included passive stretching, range-of-motion exercises, facilitated voluntary movements, balance and gait training, endurance exercises, and functional tasks. Occupational therapy focused on self-care activities and improving daily living skills. Patients had a 45–60 minute rest period between sessions. If necessary, speech therapy was provided three times weekly during both inpatient and outpatient rehabilitation.
Stroke severity was assessed using the NIHSS, which scores various neurological deficits on a scale of 0–42, with higher scores indicating greater impairment. Patients were stratified into severity levels: very severe (>25), severe (15–24), moderately severe (5–14), and mild (1–5). The primary outcome measure was the Action Research Arm Test (ARAT), which evaluates upper limb function, coordination, and dexterity. The test consists of 19 tasks across four domains including grasp, grip, pinch, and whole-hand movement, scored on a four-point scale from 0–3, with a maximum score of 57. Scores below 10 indicate poor recovery, 10–56 suggest moderate recovery, and 57 represents full functional recovery [2].
Secondary outcome measures included the Fugl-Meyer Assessment (FMA) and the Barthel Index (BI). The FMA assesses motor function, with the upper extremity subscale scoring voluntary and synergistic movements up to a maximum of 66 points. The BI evaluates independence in activities of daily living, scoring patients based on the level of assistance required. It includes ten daily living tasks, with a maximum score of 100 indicating full independence and 0 representing total dependence. All outcomes were measured at baseline, immediately after treatment on day 21, and on day 90 by a physiotherapist experienced in neurorehabilitation who was blinded to treatment assignments [2].

Discussion
1) The results of the study conducted by the research team of Chang et al revealed that the mean NIHSS score at baseline was 7.6 ± 5.4, with no significant group differences in general characteristics, stroke features, initial thrombolysis therapy, or motor function assessments. While hypertension and arrhythmia were more frequent in the Cerebrolysin group, and hyperlipidemia, coronary artery disease, and small vessel occlusion were more common in the placebo group, these differences were not statistically significant. Neglect presence was similar between the groups. Subgroup analyses of patients with severe and moderate motor impairment at baseline showed no significant differences in initial characteristics [1].
Both groups exhibited significant Fugl-Meyer Assessment (FMA) improvements over time in the ITT-LOCF analysis, but repeated measures ANOVA indicated no significant interaction between time and intervention type for FMA total, upper limb, or lower limb scores. At T3, no significant differences in FMA improvements were found between groups, though FMA total and FMA upper limb improvements tended to be greater in the Cerebrolysin group without reaching statistical significance.
Subgroup analysis of patients with severe motor impairment at baseline revealed a significant interaction effect between time and intervention type for FMA total and FMA upper limb. At T2 and T3, significant group differences in FMA total and FMA upper limb were observed, with greater improvements in the Cerebrolysin group. Regression analysis showed a strong relationship between FMA total at T0 and T3 in both groups. However, improvement in FMA total at T3 showed no relationship with baseline scores in the Cerebrolysin group, while the placebo group demonstrated a tendency towards a relationship. In contrast, subgroup analysis of patients with moderate motor impairment at baseline showed no significant time-intervention interaction effects for any FMA scores [1].

Figure 1: Changes in Fugl Meyer Assessment scores in response to administration of 30 ml of Cerebrolysin and a placebo compound, measured at baseline, immediately after treatment, after 2 months, and after 3 months. Analysis included the scores collected from 66 patients, 34 Cerebrolysin, 32 placebo, and a severe motor impairment subgroup of 37 patients. Cerebrolysin significantly improved FMA total, upper limb, and lower limb scores compared to placebo. Regression analysis showed no relationship between baseline and final FMA scores in the Cerebrolysin group, unlike the placebo group, indicating greater functional recovery with Cerebrolysin.
Diffusion tensor imaging analysis of the corticospinal tract in the severe motor impairment subgroup revealed significant time-intervention interactions for axial diffusivity and radial diffusivity. At T3, significant differences were noted between groups for axial diffusivity and radial diffusivity, favoring the Cerebrolysin group. However, no significant interaction effects were observed for fractional anisotropy . In the moderate motor impairment subgroup, diffusion tensor imaging analysis showed no significant time-intervention interactions for fractional anisotropy, axial diffusivity, or radial diffusivity [1].

Figure 2: Changes in diffusion tensor imaging in response to administration of 30 ml of Cerebrolysin and a placebo compound, measured at baseline, immediately after treatment, after 2 months, and after 3 months. The study used an intention-to-treat analysis with the last observation carried forward approach for missing data in patients with severe motor impairment determined by an FMA score of <50. It assessed changes in fractional anisotropy, axial diffusivity, and radial diffusivity over time. Results showed significant within-group, between-group, and time-dependent differences using repeated measures ANOVA.
rsfMRI analysis included 29 severe motor impairment patients. Across time, increased symmetric functional connectivity between bilateral primary sensorimotor cortices was specifically observed in the Cerebrolysin group. While repeated measures ANOVA found no significant time-intervention interaction for the lateralization index between sensory motor cortices, only the Cerebrolysin group showed significant changes in lateralization index at T1 and T3, indicating enhanced sensorimotor network symmetry.
Overall, while both groups improved in motor function, significant benefits of Cerebrolysin were observed primarily in the subgroup with severe motor impairment, as evidenced by greater FMA total and FMA upper limb improvements, enhanced corticospinal tract integrity, and increased functional connectivity in sensorimotor networks. These findings suggest that Cerebrolysin may be particularly beneficial for patients with more severe initial motor deficits following stroke [1].
2) The study conducted by the research team of Mitrović et al aimed to investigate the effects of a three-week intravenous administration of Cerebrolysin in addition to conventional rehabilitation treatment for patients in the early stages of severe subacute stroke. The findings revealed that the inclusion of Cerebrolysin reduced motor impairment in the paretic upper extremity and enhanced functional abilities more effectively than rehabilitation alone. The study focused on patients with severe motor impairment in the early subacute post-stroke phase, a period characterized by heightened plasticity and neural reorganization. This phase is crucial for rehabilitation interventions, as it presents an optimal window for modifying recovery patterns. Some research suggests that intensive rehabilitation immediately after a stroke may not be beneficial but becomes effective during the subacute phase [2].
Neuroplasticity increased spontaneously during early post-stroke rehabilitation but tended to plateau after three to six months, especially in severely impaired patients. Most functional recovery within three months was attributed to motor learning adaptation strategies. The ideal neuropharmacological agent should simultaneously promote neuroprotection and neuroplasticity. Cerebrolysin is one such multimodal drug, which, when combined with rehabilitation therapy, has shown significant benefits in patients with severe neurological damage during the early subacute stroke phase.
The results of this study align with previous research demonstrating Cerebrolysin’s positive impact on motor function in patients with high baseline stroke severity. In this study, the Cerebrolysin group showed a greater improvement in the National Institutes of Health Stroke Scale (NIHSS) score compared to the placebo group. At 90-day follow-up, the Cerebrolysin group had improved by 5.6 points on the NIHSS, while the placebo group improved by only 3.0 points. A meta-analysis of nine randomized trials also supported the efficacy of Cerebrolysin, demonstrating significant improvements in NIHSS scores [2].
Patients in this study had severe baseline motor impairments, yet the Cerebrolysin group showed significant improvements in upper limb function, as measured by the Fugl-Meyer Assessment (FMA) for the Upper Extremity and the Action Research Arm Test (ARAT). The improvements were evident after three weeks of treatment and sustained after 90 days. A third of the patients in the Cerebrolysin group achieved an FMA upper extremity score greater than 25 at follow-up, whereas no patients in the placebo group reached this threshold. These findings suggest that Cerebrolysin contributed to meaningful recovery, shifting some patients from severe to moderate-to-severe impairment.
Although the placebo group also showed improvements, likely due to rehabilitation, the gains were less pronounced than in the Cerebrolysin group. The most significant recovery window for stroke rehabilitation is within the first three months, which may explain the overall progress in both groups. Additionally, the Cerebrolysin group demonstrated significantly better outcomes in the Barthel Index (BI), a measure of functional independence. A higher proportion of patients in this group transitioned from severe to moderate dependence in daily activities, reflecting broader improvements in physical abilities and quality of life [2].
However, some clinical studies have presented mixed evidence regarding Cerebrolysin’s effectiveness in acute ischemic stroke. A recent meta-analysis found no statistically significant benefits of Cerebrolysin on the modified Rankin Scale (mRS), BI, or safety outcomes compared to placebo, indicating that while Cerebrolysin appears safe, its benefits for acute stroke patients remain uncertain. The overall effect on NIHSS scores has also been inconsistent across studies, with some showing benefits and others reporting neutral results. Another meta-analysis of seven randomized controlled trials found that Cerebrolysin did not reduce the risk of death but increased non-fatal side effects.
The methodological differences between the present study and those included in previous meta-analyses may explain the variation in results. This study focused on patients with more severe impairments in the subacute phase, rather than the acute phase, and used a longer rehabilitation treatment period. The duration of rehabilitation appears to be a critical factor, as extended therapy maximized Cerebrolysin’s potential benefits. The findings suggest that Cerebrolysin, when used in conjunction with intensive rehabilitation, can significantly improve motor and functional recovery in patients with severe post-stroke impairments [2].

 

Disclaimer

**LAB USE ONLY**
*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citations

[1] Chang WH, Park CH, Kim DY, Shin YI, Ko MH, Lee A, Jang SY, Kim YH. Cerebrolysin combined with rehabilitation promotes motor recovery in patients with severe motor impairment after stroke. BMC Neurol. 2016 Mar 2;16:31. doi: 10.1186/s12883-016-0553-z. PMID: 26934986; PMCID: PMC4776414.

[2] Mitrović SZ, Konstantinović LM, Miler Jerković V, Dedijer-Dujović S, Djordjević OC. Extended Poststroke Rehabilitation Combined with Cerebrolysin Promotes Upper Limb Motor Recovery in Early Subacute Phase of Rehabilitation: A Randomized Clinical Study. Medicina (Kaunas). 2023 Feb 3;59(2):291. doi: 10.3390/medicina59020291. PMID: 36837492; PMCID: PMC9958781.

 

 

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