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Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG-binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a neu...
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Rett syndrome (RTT) is a neurodevelopmental disorder that results from mutations in the X-linked gene for methyl-CpG-binding protein 2 (MECP2). The underlying cellular mechanism for the sensory deficits in patients with RTT is largely unknown. This study used the Bird mouse model of RTT to investigate sensory thalamocortical synaptic transmission i...
Rett syndrome (Rett) is the leading genetic cause of mental retardation in females. Most cases of Rett are caused by loss-of-function mutations in the gene coding for the transcriptional regulator methyl-CpG binding protein 2 (MeCP2), but despite much effort, it remains unclear how a loss of MeCP2 function generates the neurological deficits of Ret...
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... Twenty-days of treatment with CBL led to a significant decrease in theta and tentative increase in beta spectral power in the resting frontocentral EEG spectra of patients with RTT, thus reducing differences from the EEG spectra of typically developing peers. The positive effect of CBL on RTT symptoms has also been found in Mecp2-deficient animals [234]. ...
Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.
... Cerebrolysin (EVER Neuro Pharma GmbH, Unterach, Austria) is an intravenously administered preparation of low-molecular weight neuropeptides of less than 10 kDa (80%) and free amino acids (20%) derived from porcine brain tissue. It is a brain-specific pleiotropic agent that is proposed to target multiple ischemic pathophysiological events due to the combined action of its constituent neurotrophic factors [18][19][20][21][22][23][24][25][26][27][28][29]. Its neuroprotective properties have been demonstrated in both in vitro and murine ischemic stroke models. ...
... They include anti-apoptosis, mitigating glutamate excitotoxicity, reducing free oxygen radical concentrations, microglial activation and neuroinflammatory response modulation [19-23, 25-27, 30]. Cerebrolysin has also been shown to enhance neuroplasticity by synaptic remodeling and promoting neurogenesis in the peri-infarct zone [18,20,24,29,31]. ...
... Another frequently proposed reason for the neutral results of numerous clinical SAH trials is that candidate neuroprotective agents often addressed a single process in the neuronal ischemic cascade [68,69]. In contrast, Cerebrolysin targets multiple pathophysiological events [18][19][20][21][22][23][24][25][26][27][28][29]. The exact mechanisms of action are unknown, but preclinical studies have suggested that Cerebrolysin's neuroprotective properties are mediated via enhanced anti-apoptosis, regulation of glutatmate excitotoxicity and neuroinflammation [21,23,25,27,28,30]. ...
Asbtract
Background
There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients.
Methods
This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI).
Results
No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43–5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79–15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28–2.59).
Conclusions
Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients.
Clinical trial registration
Name of Registry: ClinicalTrials.gov
Trial Registration Number: NCT01787123.
Date of Registration: 8th February 2013.
... [47,48] In contrast, Cerebrolysin is the only brain-specific pleiotropic drug that targets multiple ischemic pathophysiological events, including counteracting glutamate excitotoxicity, neuroinflammation and apoptosis, due to the combined action of its several constituent neurotrophic factors. [18][19][20][21][22][23][24][25][49][50][51][52] The exact mechanisms of action are unknown, but several preclinical studies have suggested that Cerebrolysin not only possesses neuroprotective properties during the acute stroke period, but may also enhance neurorestoration during the poststroke recovery phase. [24,26,28,32,53,54]. ...
... For the latter, neuroplasticity manifested by synaptic remodeling and facilitated synaptic transmission have been observed. [52,55] Murine ischemic stroke model studies have also detected Cerebrolysin-induced neural progenitor cell proliferation at the subventricular zone and neurogenesis with oligodendrogenesis in the peri-infarct zone by activation of the Sonic hedgehog and PI3K/Akt signaling pathways. [25,49,50] To our knowledge this is the first study in the literature to investigate the role of Cerebrolysin for aneurysmal SAH. ...
Background
There are limited treatment options for aneurysmal subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia, a major determinant of mortality and morbidity. Cerebrolysin, a brain-specific pleiotropic neuroprotective agent, has been suggested to improve functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of Cerebrolysin for conferring such benefits in SAH patients.
Methods
This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. 50 patients received either daily Cerebrolysin (30ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Score (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the occurrence of adverse effects, six-month mortality, the occurrence of cerebral vasospasm, delayed cerebral ischemia and infarction.
Results
No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 0.53; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for good six-month recovery indicated by a modified Rankin Scale of 0 to 2 (OR: 0.53; 95% CI 0.43-5.17) and a Barthel Index of 70 or more (OR: 0.52; 95% CI: 0.29-12.72) were also similar for both groups. There was a significantly lower risk of three- and six-month mortality for patients that received Cerebrolysin (OR: 0.46; 95% CI: 0.33-0.63). There were no deaths in the Cerebrolysin group, but the morality rate for the control group was 16% (4/25). The commonest cause of death was due to delayed cerebral ischemia. There were no differences in the overall incidence of delayed cerebral ischemia (p-value: 0.78), cerebral vasospasm (p-value: 0.16) and infarction (p-value: 0.77) between the two groups.
Conclusions
Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. Results suggest a benefit in reducing three- and six-month mortality. Due to the exploratory nature of this study and its small sample size, these findings should be confirmed in a larger-scale clinical trial.
... Cerebrolysin® is a neuropeptide preparation that mimics the action of endogenous neurotrophic factors by protecting the brain against the detrimental impact of the ischemic cascade and by augmenting cerebral reorganization processes. Preclinical studies have shown a modulatory effect of Cerebrolysin® on neuroplasticity such as synaptic remodeling [3][4][5] and facilitated synaptic transmission [6][7][8][9], neurite outgrowth [10,11], oligodendrogenesis [12,13], and neurogenesis [14][15][16][17][18][19], and a beneficial effect on endogenous brain recovery processes [13][14][15]17,19]. In experimental stroke, we and others have demonstrated that treatment acute stroke with Cerebrolysin® dose dependently reduces ischemic lesion volume and neurological deficits. ...
Background:
Our previous work in acute ischemic stroke and TBI models focused on efficacy and pharmacological parameters of Cerebrolysin®. In this prospective, randomized, blinded, placebo-controlled study we compared efficacy of neuropeptide preparations with putative neurotrophic potential to the reference product Cerebrolysin® by assessing functional outcome and lesion volumes after embolic stroke in a rodent model.
Methods:
Male Wistar rats were subjected to embolic right middle cerebral artery occlusion and were treated with: 1) Cognistar® (Cerebroprotein Hydrolysate) 2.5 ml/kg, 2) Cerebrolysat® 2.5 ml/kg, 3) Cortexin® 1.7 mg/kg, 4) Cerebrolysin® 2.5 ml/kg, or 5) 1 ml of saline according to a pre-generated randomization plan. Dosages were defined according to the packet leaflet of the corresponding preparation and were adapted to the animal model as previously described. All enrolled rats received intraperitoneal injections once daily for 10 consecutive days, starting 4 h after occlusion. Functional outcome was assessed once weekly over four weeks by using a battery of behavioral tests. Infarct volume was measured four weeks after occlusion. Generalized Estimation Equations (GEE) was performed to study the treatment effect on overall functional recovery at day 28 (primary outcome), compared to saline controls.
Results:
Similar functional outcome was observed for saline control, Cognistar®, Cerebrolysat® and Cortexin®; in contrast, a significantly improved neurological outcome was observed with Cerebrolysin® treatment in comparison to saline as well as to the comparator drug treatment (p < .002). However, there was no significant difference in lesion volumes between rats treated with either Cortexin® (33.5 ± 1.9%), Cerebrolysat® (28.5 ± 2.4%), Cognistar® (34.7 ± 2.0%), or Cerebrolysin® (26.5 ± 2.3%) compared to saline-treated rats (30.8 ± 2.1%).
Conclusion:
Among all tested neuropeptide preparations, Cerebrolysin® was the only agent that was associated with a significant improvement of neurological outcome after stroke.
... Because of the complex MeCP2 mutant/wild-type mosaicism observed in Mecp2 mutant female mice, the majority of RTT preclinical therapy trials in mice are performed only on Mecp2 null male mice lacking MeCP2 in all cells (45)(46)(47)(48)(49)(50). Reasons cited for only testing Mecp2 null males include the obvious phenotype (death by 8-12 weeks) and the lack of confounding X-chromosome inactivation mosaicism. ...
Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1 deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory, and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wildtype littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio (RER), but decreased food intake compared to wildtype. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulate early and progressive metabolic and motor phenotypes of human RTT.
... Because of the complex MeCP2 mutant/wild-type mosaicism observed in Mecp2 mutant female mice, the majority of RTT pre-clinical therapy trials in mice are performed only on Mecp2 null male mice lacking MeCP2 in all cells (42)(43)(44)(45)(46)(47). Reasons cited for only testing Mecp2 null males include the obvious phenotype (death by 8-12 weeks) and the lack of confounding X chromosome inactivation mosaicism. ...
Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1 deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory, and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio (RER), but decreased food intake compared to wildtype. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulate early and progressive metabolic and motor phenotypes of human RTT.
... Results of the study suggest that the neurotrophic role of CBL, to some extent, may be due to the stabilizing effect of CBL on the microtubule-associated protein MAP2 [25]. Evidences also indicated that CBL could have more additional effects: such as increasing the levels of MAP2 expression in models of excitotoxicity, regulatory effect on energy metabolism, reducing the extent of inflammation, and neuronal death in pathological condition. ...
Gross motor dysfunction is considered as the most challenging problem in cerebral palsy (CP). It is proven that improvement of gross motor function could reduce CP-related disabilities and provide better quality of life in this group of patients. Therefore, the aim of this trial is to evaluate the effectiveness of cerebrolysin (CBL) on gross motor function of children with CP who are undergoing treatment. In this clinical trial study, paediatric patients aged 18-75 months with spastic diplegic or quadriplegic cerebral palsy, who were under rehabilitation therapy, were selected and randomly allocated in control and CBL groups. Patients in CBL group underwent treatment with standard rehabilitation therapy plus CBL. The latter was administrated intramuscularly as a single daily dose of 0.1 cc/kg for 10 days and then continued weekly for 4 months. Gross motor function of participants in the two studied groups, before and after trial, was evaluated and compared using the validated Persian version of gross motor function classification system-expanded and revised (GMFCS-E&R). During this trial, 108 patients with CP were evaluated for eligibility. From these, 50 patients were enrolled and randomly allocated in the CBL and control groups. Four months after trial, the mean level of GMFCS decreased significantly in the two groups (P < 0.05). However, it was significantly lower in the CBL group than in the control group (2.1 vs. 3.16, P < 0.05). The results of this trial indicated that CBL could improve gross motor function in patients with CP. This finding is consistent with neurotrophic and neuroprotective effects of CBL, which have been reported in various clinical trials in other neurological disorders. Further studies are recommended to establish the value of continued neuroprotection and to determine the pharmacokinetics/dynamics of CBL in this group of patients.
... Treatment of the Parkinsonian animals with CBL decreased the central square and freezing durations and increased grooming behavior. These results are in accordance with several studies that indicated that CBL improved the motor function in rats and transgenic mice [49][50][51] and increased the locomotor activity in aged mice [52,53]. ...
Aims:
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease affecting the population. The present study investigates the potential therapeutic effect of cerebrolysin (CBL), as a neurotrophic factor mimic, on the behavioral and biochemical alterations induced in 6- hydroxydopamine (6-OHDA) - lesioned rats as a model of PD.
Main methods:
The animals were divided into 3 experimental groups; control group, Parkinsonian model group through bilateral microinjection of 6-OHDA into substantia nigra (SN) and CBL-treated group which received a daily intraperitoneal administration of CBL (2.5ml / kg) initiated 24h after induction of Parkinsonism for 21days.
Key findings:
Treatment of Parkinsonian animals with CBL succeeded in restoring the midbrain and striatum dopamine levels. In addition, it normalized the increased MDA and NO levels recorded in the Parkinsonian animals and replenished the decreased level of midbrain GSH. In addition to the recorded recovery of the biochemical parameters, there was a parallel improvement in the animal's behavioral aspects.
Significance:
The findings of the present study provide evidence for the promising therapeutic effect of CBL in the present 6-OHDA rat model of PD through counteracting oxidative stress, replenishing dopamine content and enhancing behavioral outcomes.
... Treatment of the Parkinsonian animals with CBL decreased the central square and freezing durations and increased grooming behavior. These results are in accordance with several studies that indicated that CBL improved the motor function in rats and transgenic mice [49][50][51] and increased the locomotor activity in aged mice [52,53]. ...
... Although the most significant effects of CBL in the hAPP tg mice were on NGF, we also detected increased expression of GDNF. This, in combination with the CNTF-and FGF-like effects of CBL and its peptide derivatives (Chen et al., 2007;Blanchard et al., 2010a,b;Chohan et al., 2011;Rockenstein et al., 2011a), might account for the neurotrophic effects of CBL in other brain regions such as the hippocampus and the neocortex (Doppler et al., 2008). ...
Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro-nerve growth factor (NGF), NGF, brain-derived neurotrophic factor (BDNF), neurotropin (NT)-3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro-NGF were increased in saline-treated hAPP tg mice. In contrast, CBL-treated hAPP tg mice showed levels of pro-NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL-treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75(NTR) immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline-treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons. © 2012 Wiley Periodicals, Inc.
