The aim of this study is to evaluate radioprotective effects of Cerebrolysin (CBL) in rats' brain tissues after local irradiation. CBL has demonstrated antioxidant, anti-inflammatory, and tissue repair properties. In this study, the radioprotective effects of CBL in the brain tissues of rats after Irradiation (IR) (50 mg/ kg) were evaluated. The levels of different oxidative stress markers, including malondialdehyde (MDA), nitric oxide (NO), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD) were examined after treatment with radiation and CBL. First, 20 male adult Wistar rats weighing 180-200 g were used. The animals were exposed to a single fraction of 15Gy using a linear accelerator unit at a dose rate of 200 cGy/mine. In this study, to check the amount of oxidative stress following the IR, the level of four markers MDA, NO, GPx, CAT, and SOD were examined and measured using the spectrophotometric method and purchased kits. The results showed that compared to the IR group, the administration of CBL increases the levels of GPX and SOD significantly (p < 0.05). Our finding suggests that CBL has radioprotective effects on the brain by enhancing antioxidant defense mechanisms.

Context/objective Spinal cord injury (SCI) is a severe condition characterized by neuronal apoptosis and inflammation, with limited therapeutic options. This study aimed to assess the effects of platelet-rich plasma (PRP)-derived exosomes (Exo), Cerebrolysin (CBL), and Cerebrolysin-loaded exosomes (CLE) on inflammation, apoptosis, tissue organization, and motor function recovery in a mouse model of compression SCI. Design An experimental study using a mouse model of SCI, investigating the effects of Exo, CBL, and CLE treatments. Setting Laboratory-based research in a controlled environment. Participants Sixty healthy adult female BALB/c mice, aged 8–10 weeks, weighing 24 ± 2 g were used. SCI was induced via compression to model SCI. Interventions Mice with induced SCI were treated with Exo, CBL, or CLE. Apoptosis was assessed by Bax and Bcl2 expression. Inflammatory markers TNF-α and IL-10 were measured. Histological analysis examined tissue organization, and motor function recovery was evaluated using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Outcome measures The study measured Bax and Bcl2 expression, TNF-α and IL-10 levels, tissue organization, and motor function recovery. Results CLE treatment significantly modulated Bax and Bcl2 expression, reducing apoptosis and enhancing neuronal survival. TNF-α levels decreased, indicating reduced inflammation, while IL-10 levels increased, showing anti-inflammatory effects. Histological assessment revealed improved tissue organization, and motor function recovery was significantly enhanced as measured by BBB scores. Conclusion CLE showed neuroprotective and anti-inflammatory effects, reducing apoptosis and inflammation while promoting tissue repair and motor function recovery in SCI, making it a promising therapeutic candidate.

BackgroundThe occurrence of delirium in the first days after cardiac surgery is associated with a worse prognosis. We studied the effect of cerebrolysin (CBL) given to patients undergoing elective coronary artery bypass grafting surgery (CABG) under extracorporeal circulation, on the postoperative results in the Montreal Cognitive Assessment score (MoCA) results, and the rate of delirium detected by using the Confusion Assessment Method (CAM).Material/MethodsAdult patients undergoing elective CABG surgery under propofol-based anesthesia were divided into 2 groups: the study group received 50 ml of CER preoperatively and on the 4 subsequent consecutive days, and the control group did not receive CER. MoCA was used to assess cognition, and CAM was applied to detect delirium. Both tests were performed preoperatively, as well as on the 2nd and 5th postoperative days.ResultsThe study [n=29] and control [n=26] groups were well-balanced in terms of basic demographic, psychological, and clinical variables. Although significantly lower values of the MoCA (medians: 27 vs 24, respectively; P=0.0083) were detected in the study group in the second assessment, the pre- and postoperative MoCA values did not differ between the analyzed groups. Delirium occurred in 3 cases, and only in the control group, and the difference was not statistically significant.ConclusionsPatients maintained their cognitive status. The lack of delirium in the study group prompts us to develop a plan for a large-scale multicenter study assessing the potential ability of CER to reduce the risk of delirium in cardiac surgery patients.

The possible role of cerebrolysin in the management of vascular dementia: Leveraging concepts.

Cerebrolysin treatment improved short-term memory deficits while simultaneously increasing hippocampal spine density in hypertensive female rats.

Lesions in the motor cortex induced by contusions or pathological insults can exert the degeneration of afferent neurons lying distal to these lesions. Axon degeneration and demyelination are hallmarks of several diseases sharing pathophysiological and clinical characteristics. These conditions are very disabling due to the disruption of motor abilities, with lesions that affect this area proving to be a therapeutic challenge, which has driven increasing efforts to search for treatments. Cerebrolysin (CBL) contains a mix of pig brain-derived peptides with activity similar to neurotrophic factors. Here, the effect of cerebrolysin administration on the motor impairment produced by kainic acid (KA) lesion of the motor cortex was evaluated in Sprague-Dawley female rats (n = 27), defining its effect on motoneurons dendritic tree changes, dendritic spine density and GAP43 presence in the ventral thoracolumbar regions of the spinal cord. Ten days after the KA lesion of the motor cortex, rats were administered cerebrolysin, and their motor performance was evaluated using the "Basso, Beattie, and Bresnahan" (BBB) and Bederson scores. Cerebrolysin administration improved motor activity according to the BBB and Bederson scales, along with increased dendritic intersections and dendritic spine density on motoneurons. There was also a significant increase in GAP43 protein, suggesting that CBL may promote plastic changes through this protein, among others. Hence, this study proposes that cerebrolysin could promote motor recovery following motor cortex lesions by driving neuronal changes and dendritic spine plasticity on motoneurons and an increase in GAP43 protein, along with other mechanisms.

The administration of Cerebrolysin elicits neuroprotective and neurorepair effects in an animal model of type 1 diabetes mellitus

Acute Combined Cerebrolysin and Nicotinamide Administration Promote Cognitive Recovery Through Neuronal Changes in the Hippocampus of Rats with Permanent Middle Cerebral Artery Occlusion

BackgroundSpinal cord injury (SCI) is widely considered the most disastrous medical condition. With no available treatment to date, SCI continues to cause disabilities to the patients and affect their own and their caregivers' quality of life. Cerebrolysin (CBL) is a neuropeptide preparation derived from purified brain proteins with suggested neuroprotective and neurotrophic properties. CBL showed earlier the ability to target multiple pathways that helped in the improvement of the recovery following different groups of neurological diseases and injuries, including ischemic stroke, traumatic brain injuries, and even neurodegenerative diseases. In the current study, the neuroprotective effect of CBL following a SCI is called into question using a rat model of spinal cord cervical hemi-section validated earlier by our lab and others. Using 32 rats divided into four groups randomly, CBL treatment was implemented for either 7 or 21 days duration, following the cervical spinal cord hemi-section.ResultsFollowing the CBL treatment, rats with cervical cord hemi-section showed functional improvement of diaphragmatic muscle as recorded by electromyography (EMG). In addition, the histopathological assessment of the spinal cord showed improved neuronal viability and reduced astrogliosis at the site of the injury compared to the non-treated group. 21-day treatment showed significant improvement when compared to the shorter 7-day regimen.ConclusionOur data suggest that CBL is capable of protecting and regenerating anterior horn motor neurons with functional recovery of diaphragmatic muscle functions in rats, suggesting the potential use of CBL for future regenerative and neuroprotective therapy following SCI.

Forebrain ischemia-reperfusion (IR) injury causes neurological impairments due to decreased cerebral autoregulation, hypoperfusion, and edema in the hours to days following the restoration of spontaneous circulation. This study aimed to examine the protective and/or therapeutic effects of cerebrolysin (CBL) in managing forebrain IR injury and any probable underlying mechanisms. To study the contribution of reperfusion to forebrain injury, we developed a transient dual carotid artery ligation (tDCAL/IR) mouse model. Five equal groups of six BLC57 mice were created: Group 1: control group (no surgery was performed); Group 2: sham surgery (surgery was performed without IR); Group 3: tDCAL/IR (surgery with IR via permanently ligating the left CA and temporarily closing the right CA for 30 min, followed by reperfusion for 72 h); Group 4: CBL + tDCAL/IR (CBL was given intravenously at a 60 mg/kg BW dose 30 min before IR); and Group 5: tDCAL/IR + CBL (CBL was administered i.v. at 60 mg/kg BW three hours after IR). At 72 h following IR, the mice were euthanized. CBL administration 3 h after IR improved neurological functional recovery, enhanced anti-inflammatory and antioxidant activities, alleviated apoptotic neuronal death, and inhibited reactive microglial and astrocyte activation, resulting in neuroprotection after IR injury in the tDCAL/IR + CBL mice group as compared to the other groups. Furthermore, CBL reduced the TLRs/NF-kB/cytokines while activating the Keap1/Nrf2/antioxidant signaling pathway. These results indicate that CBL may improve neurologic function in mice following IR.

Optimized approach for active peptides identification in Cerebrolysin by nanoLC-MS

Posttraumatic stress disorder (PTSD) is a serious neuropsychiatric disorder that occurs after exposure to stressful, fearful, or troubling events. Cerebrolysin (CBL), consists of low molecular weights neurotrophic factors and amino acids obtained from purified porcine brain proteins. This study aimed to evaluate the possible therapeutic effects of enriched environment (EE) and CBL alone or combined for reducing anxiety and cognitive deficits in PTSD-like mouse models. For this purpose, inescapable electric foot shocks were delivered to Balb/c mice for two consecutive days. Then mice were treated with CBL (2.5 mL/kg) and/or were kept in EE (2 h per day) or received their combination for 14 consecutive days. The hole-board test and Lashley III paradigm were used to assess anxiety and spatial learning and memory, respectively. Changes in the serum corticosterone level and expression of synaptic elements, including; growth-associated protein 43, post-synaptic density 95, and synaptophysin were assessed in the hippocampus. This model caused anxiety and spatial memory impairment associated with increased serum corticosterone levels and decreased synaptic elements. Nevertheless, CBL and/or combination treatment could reverse behavioral and molecular alterations. Our findings indicated that CBL, separately or in combination with EE, is effective in reducing anxiety and spatial memory impairment in PTSD-like mice.

Cerebrolysin (CBL) is a porcine brain-derived preparation with noticeable neurotrophic and neuroprotective activity. Treatment with CBL has significant potential to treat various debilitating neurological diseases such as traumatic brain injuries, ischemic stroke, and spinal cord injury. Although using CBL is not approved in the United States, about 50 countries have used it in clinics. CBL is a drug similar to neurotrophins with a multimodal action that effectively helps the central nervous system (CNS) and brain function properly through the protection, maintenance, and regeneration of the neural system. Furthermore, the safety and efficacy of CBL were approved following several clinical trials. Recent studies have shown its neurorecovery potential besides the neuroprotection ability. In addition, CBL efficacy has been reported in patients with moderate-to-severe strokes. A significant effect of CBL was observed in combination with neurorehabilitation versus neurorehabilitation alone. Following spinal cord injury (SCI), a cascade of neurochemical alteration happens in neural cells, including a reduction in producing neurotrophic and growth factors that lead to neural death. Previous studies indicated that exogenous compounds and supplements of different NTFs improve the spinal cord neuroprotection after injury. Among the existing drugs, CBL could be a valuable candidate, a compound mixture of various NTFs with multimodal action.

Effects of cerebrolysin (CBL) on prooxidant-antioxidant balance and oxidative stress (OS) developing in blood of patients with Parkinson’s disease (PD) were studied. Twenty patients with PD and 10 healthy persons (control) participated in this study. Clinical diagnosis of PD was established according UK Brain Bank Criteria; the grades of PD were II-III after Hoehn/Yahr. PD patients received therapy with CBL administration intravenously at dose 20 ml (61.5 mg/kg) per day along 10 days. As OS biomarkers, lipid peroxidation (from the formation of thiobarbituric acid – reactive substances, TBARS), H2O2 production, the activities of SOD, catalase, and GPx, as well as glutathione pool indexes were measured in blood plasma and erythrocytes. It was established a significant rise in TBARS in plasma and H2O2 contents in erythrocytes from patients with PD compared to control. These events were accompanied by an increase in the SOD and catalase activities in plasma and a decrease in GSH content and GPx activity in erythrocytes. CBL administration counteracts the TBARS accumulation, reduces hyperactivation of SOD and catalase in plasma compared with the CBL-untreated patients. In erythrocytes of PD patients, CBL injection caused the limitation of H2O2 production as well as promotion the GSH pool recovery through an increase in GSH level and GPx activity.

Cerebrolysin® and Environmental Enrichment, Alone or in Combination, Ameliorate Anxiety- and Depressive-Like Behaviors in a Post-Ischemic Depression Model in Mice

ABSTRACTPurpose:Traumatic brain injury (TBI) is a major cause of death and disability. Cerebrolysin (CBL) has been reported to be anti-inflammatory by reducing reactive oxygen species (ROS) production. However, the neuroprotection of CBL in TBI and the potential mechanism are unclear. We aimed to investigate the neuroprotection and mechanisms of CBL in TBI.Methods:The TBI model was established in strict accordance with the Feeney weight-drop model of focal injury. The neurological score, brain water content, neuroinflammatory cytokine levels, and neuronal damage were evaluated. The involvement of the early brain injury modulatory pathway was also investigated.Results:Following TBI, the results showed that CBL administration increased neurological scores and decreased brain edema by alleviating blood‑brain barrier (BBB) permeability, upregulating tight junction protein (ZO‑1) levels, and decreasing the levels of the inflammatory cytokines tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), IL‑6, and NF‑κB. The TUNEL assay showed that CBL decreased hippocampal neuronal apoptosis after TBI and decreased the protein expression levels of caspase‑3 and Bax, increasing the levels of Bcl‑2. The levels of Toll‑like receptor 2 (TLR2) and TLR4 were significantly decreased after CBL treatment. In TBI patients, CBL can also decrease TNF‑α, IL‑1β, IL‑6, and NF‑κB levels. This result indicates that CBL‑mediated inhibition of neuroinflammation and apoptosis ameliorated neuronal death after TBI. The neuroprotective capacity of CBL is partly dependent on the TLR signaling pathway. Conclusions:Taken together, the results of this study indicate that CBL can improve neurological outcomes and reduce neuronal death against neuroinflammation and apoptosis via the TLR signaling pathway in mice.

Chemotherapy-induced cognitive impairment (CICI) comprises different neurological problems, including difficulty in learning new things, concentrating and making decisions that affect daily life activities. Clinical reports indicate that around 70% of cancer patients receiving chemotherapy suffer from cognitive impairment. The purpose of the present study is to examine the effects of widely used anticancer medication (Carmustine) on cognitive function using mice model and investigation of the neuroprotective effects of Cerebrolysin (CBN). Cerebrolysin (CBN) is a mixture of several neurotrophic factors and active peptides with anti-inflammatory, antioxidant, and neuroprotective actions. Our study aimed to establish a mice model of Carmustine (BCNU)-induced cognitive deficits and determine the protective effects of CBN. BCNU (10 mg/kg, i.v.) was administered to mice for 28 days, and behavioral parameters were measured on a weekly basis. CBN (44 and 88 mg/kg, i.p.) was administered daily from day 1 to 28 to BCNU treatment mice. All animals were sacrificed on day 29 and brain hippocampus tissues were used for biochemical, neuroinflammatory, neurotransmitters analysis. BCNU administration animals showed impaired cognition and memory, confirmed from behavioral analysis. Further, BCNU increased oxidative stress, inflammatory cytokines release and altered neurotransmitters concentration as compared to the control group (p < 0.01). However, mice treated with CBN (44 and 88 mg/kg, i.p.) significantly and dose-dependently improved cognitive functions, reduced oxidative stress markers, inflammatory cytokines and restored neurotransmitters concentration as compared to BCNU administered mice (p < 0.05). The finding of current study suggested that CBN could be the promising compound to reverse cognitive impairment associated with use of chemotherapy.

ObjectiveTo investigate the neuroprotective effect and mechanism of cerebroprotein hydrolysate-I (CH-I) on cerebral ischemia/reperfusion injury in rats.MethodsA total of 100 adult healthy male SD rats were randomly divided into a sham group, model group, CH-I treated group, and cerebrolysin (CBL) positive group, consisting of 20 rats in each group. The middle cerebral artery occlusion/reperfusion (MCAO/R) model of rats was built by inserting a suture into the left external carotid artery (ECA) through the internal carotid artery (ICA). Treatment was performed by intraperitoneal injection of CH-I (20 mg/kg). The neurobehavioral function of rats was evaluated by modified neurological severity scores (mNSS). TTC staining was used to detect the cerebral infarction volume (CIV) of rats. The morphological and structural changes of nerve cells were observed by HE staining and the neuronal apoptosis was counted by TUNEL assay. Immunohistochemical (IHC) analysis was used to detect BDNF and pMEK1/2 expressions. The expressions of BDNF, pMEK1/2, pERK1/2, and pCREB were determined with Western blotting.ResultsAfter treatment with CH-I, the mNSS and CIV of rats were improved (P<0.05). And the CH-I can reduce the degeneration and apoptosis of nerve cells in rats (P<0.01). Western blotting showed that the expressions of pMEK1/2, pERK1/2, and pCREB in rats were increased, while the expression of BDNF was decreased after modeling (P<0.05). After treatment, the expressions of pMEK1/2, pERK1/2, and pCREB in the CH-I group were decreased (P<0.05), while the expression of BDNF was significantly increased (P<0.05) compared with the model group. IHC showed that the expression of BDNF and pMEK1/2 was consistent with Western blotting.ConclusionIt is suggested that the CH-I might play a neuroprotective role by inhibiting the expression of MEK-ERK-CREB and enhancing the expression of BDNF after cerebral ischemia/reperfusion injury, thus improving the neurobehavioral function of MCAO/R rats.

IntroductionVascular dementia (VaD), one of the brain injuries, is difficult to be cured, so it is important to take active neuroprotective treatment after its occurrence. Many studies have shown that apoptosis serves an important role in VaD occurrence; therefore, inhibition of apoptosis may contribute to the recovery of neurological function after VaD occurrence. Cerebroprotein hydrolysate-I (CH-I), a neuropeptide preparation which consists of several amino acids and small molecular peptides as the main active constituent, is extracted using a method similar to cerebrolysin (CBL) which has neuroprotective and neurotrophic effects.MethodsIn the present study, a VaD model which was constructed using bilateral common carotid artery occlusion (BCCAO) in Kunming mice was applied to examine the neuroprotective effects of CH-I.ResultsThe results show that CH-I treatment could attenuate the decrease of learning and memory ability, cell apoptosis in the hippocampal CA1 region and inhibit the activation of caspase-3 and caspase-9 in VaD mice. Furthermore, CH-I treatment could also upregulate Bcl-2 protein levels and activate PI3K and Akt.DiscussionWe speculate that CH-I may induce a neuroprotective effect activating PI3K/Akt signaling pathway in VaD mice.

ABSTRACTPurpose:Spontaneous intracerebral hemorrhage (ICH) is a major cause of death and disability with a huge economic burden worldwide. Cerebrolysin (CBL) has been previously used as a nootropic drug. Necroptosis is a programmed cell death mechanism that plays a vital role in neuronal cell death after ICH. However, the precise role of necroptosis in CBL neuroprotection following ICH has not been confirmed.Methods:In the present study, we aimed to investigate the neuroprotective effects and potential molecular mechanisms of CBL in ICH-induced early brain injury (EBI) by regulating neural necroptosis in the C57BL/6 mice model. Mortality, neurological score, brain water content, and neuronal death were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Evans blue extravasation, Western blotting, and quantitative real-time polymerase chain reaction (PCR).Results:The results show that CBL treatment markedly increased the survival rate, neurological score, and neuron survival, and downregulated the protein expression of RIP1 and RIP3, which indicated that CBL-mediated inhibition of necroptosis, and ameliorated neuronal death after ICH. The neuroprotective capacity of CBL is partly dependent on the Akt/GSK3β signaling pathway.Conclusions:CBL improves neurological outcomes in mice and reduces neuronal death by protecting against neural necroptosis.