BREAIN DERIVED NEUROTROPHIC FACTOR (BDNF)

 

https://en.wikipedia.org/wiki/Brain-derived_neurotrophic_factor

  • Brain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factorNeurotrophic factors are found in the brain and the periphery

  • BDNF acts on certain neurons of the central nervous system and the peripheral nervous system, helping to support the survival of existing neurons, and encourage the growth and differentiation of new neurons and synapses.[8][9] In the brain, it is active in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking.[10] It is also expressed in the retina, motor neurons, the kidneys, saliva, and the prostate.[11]

  • BDNF itself is important for long-term memory.[12] Although the vast majority of neurons in the mammalian brain are formed prenatally, parts of the adult brain retain the ability to grow new neurons from neural stem cells in a process known as neurogenesis. Neurotrophins are proteins that help to stimulate and control neurogenesis, BDNF being one of the most active.[13][14][15] Mice born without the ability to make BDNF suffer developmental defects in the brain and sensory nervous system, and usually die soon after birth, suggesting that BDNF plays an important role in normal neural development.[16] Other important neurotrophins structurally related to BDNF include NT-3, NT-4, and NGF.

  • BDNF is made in the endoplasmic reticulum and secreted from dense-core vesicles. It binds carboxypeptidase E (CPE), and the disruption of this binding has been proposed to cause the loss of sorting of BDNF into dense-core vesicles. The phenotype for BDNF knockout mice can be severe, including postnatal lethality. Other traits include sensory neuron losses that affect coordination, balance, hearing, taste, and breathing. Knockout mice also exhibit cerebellar abnormalities and an increase in the number of sympathetic neurons.[17]

  • Certain types of physical exercise have been shown to markedly (threefold) increase BDNF synthesis in the human brain, a phenomenon which is partly responsible for exercise-induced neurogenesis and improvements in cognitive function.[18][19][20][21] Niacin appears to upregulate BDNF and tropomyosin receptor kinase B (TrkB) expression as well.[22]

Cerebrolysin

  • A mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments.

Brain-derived neurotrophic factor (BDNF), glialderived neurotrophic factor (GDNF), nerve growth factor (NGF)

  • Cerebrolysin is a porcine (pig) brain derived peptide preparation with a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments.

  • Cerebrolysin facilitates neurotrophic activity which has been shown to improve cognitive performance and global function in numerous neurodegenerative disorders and mental illness. Significant improvement of cognitive function, clinical global impression and increased activities of daily living were observed.

  • Cerebrolysin potentiates brain alpha activity, reduces slow EEG delta frequencies and improves memory performance in healthy elderly humans, suggesting that this compound activates cerebral mechanisms related to attention and memory processes.

  • Cerebrolysin is a safe product administered either intravenous and or intramuscular injection. The oral Cerebrolysin product is not as effective as the IV and IM application but useful in ongoing treatment recommendations.

  • Cerebrolysin is a safe drug that improves the cognitive deficits and global function in patients with mild to moderate progressive neurodegenerative disease including Multiple Sclerosis, Parkinson’s Disease, Alzheimers Disease, Dementia, Acute and Chronic Stroke victims.

  • Cerebrolysin also demonstrated significant improvement in victims of post-acute traumatic brain injury.

  • Cerebrolysin demonstrated significant benefit in childhood autism (89%) and cerebral palsy (mild to complex anoxic encephalopathy).

  • Cerebrolysin protects against induced motor neuron damage and reduced imposed nerve death. Studies involving induced spinal cord and nerve root damage revealed significant motor recovery with Cerebrolysin.

  • Cerebrolysin exerts a neuro-immunotrophic activity reducing the extent of chronic nerve cell inflammation and accelerated neuronal death under pathological conditions such as those observed in acute traumatic and chronic progressive neurodegenerative diseases (progressive arthritis).

  • Cerebrolysin demonstrates ‘anti-aging’ with benefits ‘improving cognition, memory function, brain metabolism with capacity.

  • Cerebrolysin has neuroprotective and neurorestorative properties, consisting of low molecular weight peptides that are able to cross the BBB and mimic the action of endogenous neurotrophic factors.[144–146] Some of the neuropeptides contained in the Cerebrolysin concentrate demonstrated cross-reactivity with antibodies against several trophic factors (glial cell line-derived neurotrophic factor, ciliary neurotrophic factor, IGF-1 and IGF-2), suggesting their potential capacity to bind receptors of these factors.

  • Cerebrolysin acts as a multimodal drug exerting, probably through synergistic actions of its peptides, pleiotropic positive effects on Aβ and tau pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuronal apoptosis and degeneration, neuroplasticity, neurogenesis as well as cognition, as shown in experimental and human studies.[144–146]

 

In pharmacodynamic studies it has been demonstrated that Cerebrolysin:

 

  • Reduces brain Aβ deposition, tau phosphorylation and Aβ- and tau-related neuropathology by regulating GSK-3β and CDK-5 activity;[147–149]

  • Modulates neuroinflammation, attenuating microglia activation and IL-1β release in vitro and in vivo, and reducing the elevated serum levels of TNF-α and TNF receptor-1 in AD patients;[150–153]

  • Displays neurotrophic-like actions on neuronal survival and neurite outgrowth and increases circulating IGF-1 and BDNF levels in humans;[144,151,154–157]

  • Protects against oxidative and excitotoxic damage, at least in part by inhibiting lipid peroxidation and calpain activation;[158–162]

  • Influences synaptic transmission mediated by GABAB, adenosine A1 and glutamate receptor subunit 1 receptors and exhibits cholinotrophic activity;[154,157,163–166]

  • Enhances the supply of glucose to the brain and ameliorates the slowing of brain bioelectrical activity;[167–170]

  • Promotes neural plasticity and prevents dendritic and synaptic loss;[155,157,171–178]

  • Promotes neuronal survival protecting neurons from apoptosis and degeneration;[147–149,154–157,159,176–179]

  • Stimulates neurogenesis, probably through Akt activation;[180–184]

  • Improves learning and memory.[147,148,164,170,177,182,185–187]

 

Int J Neuropsychopharmacol. 2016 Apr 7. pii: pyw024. doi: 10.1093/ijnp/pyw024. [Epub ahead of print]

Synergistic Increase of Serum BDNF in Alzheimer Patients Treated with Cerebrolysin and Donepezil: Association with Cognitive Improvement in ApoE4 Cases.

Alvarez XA1, Alvarez I2, Iglesias O2, Crespo I2, Figueroa J2, Aleixandre M2, Linares C2, Granizo E2, Garcia-Fantini M2, Marey J2, Masliah E2, Winter S2,Muresanu D2, Moessler H2.

Author information

Abstract

BACKGROUND:

Low circulating brain derived neurotrophic factor may promote cognitive deterioration, but the effects of neurotrophic and combination drug therapies on serum brain derived neurotrophic factor were not previously investigated in Alzheimer's disease.

METHODS:

We evaluated the effects of Cerebrolysin, donepezil, and the combined therapy on brain derived neurotrophic factor serum levels at week 16 (end of Cerebrolysin treatment) and week 28 (endpoint) in mild-to-moderate Alzheimer's disease patients.

RESULTS:

Cerebrolysin, but not donepezil, increased serum brain derived neurotrophic factor at week 16, while the combination therapy enhanced it at both week 16 and study endpoint. Brain derived neurotrophic factor responses were significantly higher in the combination therapy group than in donepezil and Cerebrolysin groups at week 16 and week 28, respectively. Brain derived neurotrophic factor increases were greater in apolipoprotein E epsilon-4 allele carriers, and higher brain derived neurotrophic factor levels were associated with better cognitive improvements in apolipoprotein E epsilon-4 allele patients treated with Cerebrolysin and the combined therapy.

CONCLUSION:

Our results indicate a synergistic action of Cerebrolysin and donepezil to increase serum brain derived neurotrophic factor and delaying cognitive decline, particularly in Alzheimer's disease cases with apolipoprotein E epsilon-4 allele.

Synapse. 2016 Sep;70(9):378-89. doi: 10.1002/syn.21912. Epub 2016 May 30.

Cerebrolysin improves memory and ameliorates neuronal atrophy in spontaneously hypertensive, aged rats.

Solis-Gaspar C1, Vazquez-Roque RA1, De Jesús Gómez-Villalobos M1, Flores G1.

Author information

Abstract

The spontaneously hypertensive (SH) rat has been used as an animal model of vascular dementia (VD). Our previous report showed that, SH rats exhibited dendritic atrophy of pyramidal neurons of the CA1 dorsal hippocampus and layers 3 and 5 of the prefrontal cortex (PFC) at 8 months of age. In addition, we showed that cerebrolysin (Cbl), a neurotrophic peptide mixture, reduces the dendritic atrophy in aged animal models. This study aimed to determine whether Cbl was capable of reducing behavioral and neuronal alterations, in old female SH rats. The level of diastolic and systolic pressure was measured every month for the 6 first months and only animals with more than 160 mm Hg of systolic pressure were used. Female SH rats (6 months old) received 6 months of Cbl treatment. Immediately after the Cbl treatment, two behavioral tests were applied, the Morris water maze test for memory and learning and locomotor activity in novel environments. Immediately after the last behavioral test, dendritic morphology was studied with the Golgi-Cox stain procedure followed by a Sholl analysis. Clearly, SH rats with Cbl showed an increase in the dendritic length and dendritic spine density of pyramidal neurons in the CA1 in the dorsal hippocampus and layers 3 and 5 of the PFC. Interestingly, Cbl improved memory of the old SH rats. Our results support the possibility that Cbl may have beneficial effects on the management of brain alterations in an animal model with VD. Synapse 70:378-389, 2016. © 2016 Wiley Periodicals, Inc.

J Neurotrauma. 2014 Sep 15. [Epub ahead of print]

Cerebrolysin Asian Pacific Trial in Acute Brain Injury and Neurorecovery (CAPTAIN)

Poon W1, Vos PE, Muresanu D, Vester J, von Wild K, Hömberg V, Wang E, Lee T, Matula C.

Author information

1The Chinese University of Hong Kong, Division of Neurosurgery, Hong King, Hong Kong ; wpoo@cuhk.edu.hk.

Abstract

Traumatic brain injury (TBI) is one of the leading causes of injury-related death. In the USA alone, an estimated 1.7 million people sustain a TBI each year, and approximately 5.3 million people live with a TBI-related disability. The direct medical costs and indirect costs, such as lost productivity, of TBIs totaled an estimated $76.5 billion in the USA in the year 2000. Improving the limited treatment options for this condition remains challenging. However, recent reports from interdisciplinary working groups (consisting primarily of neurologists, neurosurgeons, neuropsychologists, and biostatisticians) have stated that to improve TBI treatment, important methodological lessons from the past must be taken into account in future clinical research. An evaluation of the neuroprotection intervention studies conducted over the last 30 years has indicated that a limited understanding of the underlying biological concepts and methodological design flaws are the major reasons for the failure of pharmacological agents to demonstrate efficacy. Cerebrolysin is a parenterally administered neuro-peptide preparation that acts in a manner similar to endogenous neurotrophic factors. Cerebrolysin has a favorable side-effect profile, and several meta-analyses have suggested that Cerebrolysin is beneficial as a dementia treatment. CAPTAIN is a randomized, double-blind, placebo-controlled, multi-center, multinational trial of the effects of Cerebrolysin on neuroprotection and neurorecovery after TBI using a multidimensional ensemble of outcome scales. The CAPTAIN trial will be the first TBI trial with a 'true' multidimensional approach based on full outcome scales, while avoiding prior weaknesses, such as loss of information through 'dichotomization', or unrealistic assumptions such as 'normal distribution'.

CNS Neurol Disord Drug Targets. 2014;13(8):1475-82.

Poly (D,L-Lactide-co-Glycolide) Nanoparticles Loaded with Cerebrolysin Display Neuroprotective Activity in a Rat Model of Concussive Head Injury

Ruozi B, Belletti D, Forni F, Sharma A, Muresanu D, Mossler H, Vandelli MA, Tosi G, Sharma HS1.

Author information

  • 1Director of Research, International Experimental CNS Injury & Repair, Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, University Hospital, Uppsala University, SE-75421, Uppsala, Sweden. Sharma@surgsci.uu.se.

Abstract

Cerebrolysin (CBL) is a neuroprotective agent in central nervous system (CNS) injury and stimulates neurorepair processes. Several studies in our laboratory suggest that CBL administered through nanowired technology may have superior neuroprotective efficacy in CNS trauma. In this investigation, we compared the neuroprotective efficacy of poly-lactide-co-glycolide nanoparticles (NPs) loaded with CBL vs free CBL in a rat model of concussive head injury (CHI). Free CBL or CBL loaded NPs was administered 30 min to 1 h after CHI and animals were sacrificed 5 h later. Changes in blood-brain barrier and brain edema formation were measured as parameters of neuroprotection in CHI after giving CBL alone or as the nanodelivered compound. Our results clearly show that delivery of CBL by NPs has superior neuroprotective effects following CHI as compared to normal CBL. This suggests that CBL delivered by NPs could have robust neuroprotective action in CNS trauma. These findings have potential clinical relevance with regard to nanodelivery of CBL, a feature that requires further investigation.

 

BMC Neurosci. 2014 Jul 21;15:90. doi: 10.1186/1471-2202-15-90.

Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure

Rockenstein E, Ubhi K, Trejo M, Mante M, Patrick C, Adame A, Novak P, Jech M, Doppler E, Moessler H, Masliah E1.

Author information

  • 1Department of Neurosciences, University of California San Diego, La Jolla, CA, USA. emasliah@ucsd.edu.

Abstract

BACKGROUND:

Alzheimer's Disease (AD) and Fronto temporal lobar dementia (FTLD) are common causes of dementia in the aging population for which limited therapeutical options are available. These disorders are associated with Tau accumulation. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the behavioral deficits and neuropathological alterations in amyloid precursor protein (APP) transgenic (tg) mouse model of AD by reducing hyper-phosphorylated Tau. CBL has been tested in clinical trials for AD, however it's potential beneficial effects in FTLD are unknown. For this purpose we sought to investigate the effects of CBL in a tg model of tauopathy. Accordingly, double tg mice expressing mutant Tau under the mThy-1 promoter and GSK3β (to enhance Tau phosphorylation) were treated with CBL and evaluated neuropathologically.

RESULTS:

Compared to single Tau tg mice the Tau/GSK3β double tg model displayed elevated levels of Tau phosphorylation and neurodegeneration in the hippocampus. CBL treatment reduced the levels of Tau phosphorylation in the dentate gyrus and the degeneration of pyramidal neurons in the temporal cortex and hippocampus of the Tau/GSK3β double tg mice. Interestingly, the Tau/GSK3β double tg mice also displayed elevated levels of Dynamin-related protein-1 (Drp-1), a protein that hydrolyzes GTP and is required for mitochondrial division. Ultrastructural analysis of the mitochondria in the Tau/GSK3β double tg mice demonstrated increased numbers and fragmentation of mitochondria in comparison to non-tg mice. CBL treatment normalized levels of Drp-1 and restored mitochondrial structure.

CONCLUSIONS:

These results suggest that the ability of CBL to ameliorate neurodegenerative pathology in the tauopathy model may involve reducing accumulation of hyper-phosphorylated Tau and reducing alterations in mitochondrial biogenesis associated with Tau.

Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(1 Vypusk 2 Detskaia nevrologiia i psikhiatriia):75-80.

Cerebrolysin in pediatric neurology practice

[Article in Russian]

Petrukhin AS1, Pylaeva OA.

Author information

  • 1Kafedra nevrologii, neĭrokhirurgii i meditsinskoĭ genetiki lechebnogo fakul'teta GBOU VPO "Rossiĭskiĭ natsional'nyĭ issledovatel'skiĭ meditsinskiĭ universitet im. N.I. Pirogova", Moskva.

Abstract

Мany aspects of сerebrolysin treatment in a wide range of nervous system disorders in children are described. High efficacy and well tolerated therapy are revealed. These findings expand the perspectives of using сerebrolysin in pediatric neurology.

J Neurol Sci. 2014 Feb 15;337(1-2):104-11. doi: 10.1016/j.jns.2013.11.028. Epub 2013 Nov 26.

Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction

Xing S1, Zhang J1, Dang C1, Liu G1, Zhang Y2, Li J1, Fan Y1, Pei Z1, Zeng J3.

Author information

  • 1Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China.

  • 2Department of Neurology, The First Affiliated Hospital, Jinan University, No. 613 Huangpu Avenue West, Guangzhou 510630, China.

  • 3Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China. Electronic address: zengjs@pub.guangzhou.gd.cn.

Abstract

Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot. The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (p<0.05). Aβ deposits and BACE1 were obviously reduced by Cerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p < 0.05). Coincidently, Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all p<0.05). These findings suggest that Cerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

 

PLoS One. 2013 Jun 19;8(6):e64847. Print 2013.

Cerebrolysin Ameloriates Cognitive Deficits in Type III Diabetic Rats

Georgy GS1, Nassar NN, Mansour HA, Abdallah DM.

Author information

  • 1Department of Pharmacology, National Organization of Drug Control and Research (NODCAR), Giza, Egypt.

Abstract

Cerebrolysin (CBL), a mixture of several active peptide fragments and neurotrophic factors including brain-derived neurotrophic factor (BDNF), is currently used in the management of cognitive alterations in patients with dementia. Since Cognitive decline as well as increased dementia are strongly associated with diabetes and previous studies addressed the protective effect of BDNF in metabolic syndrome and type 2 diabetes; hence this work aimed to evaluate the potential neuroprotective effect of CBL in modulating the complications of hyperglycaemia experimentally induced by streptozotocin (STZ) on the rat brain hippocampus. To this end, male adult Sprague Dawley rats were divided into (i) vehicle- (ii) CBL- and (iii) STZ diabetic-control as well as (iv) STZ+CBL groups. Diabetes was confirmed by hyperglycemia and elevated glycated haemoglobin (HbA1c%), which were associated by weight loss, elevated tumor necrosis factor (TNF)-α and decreased insulin growth factor (IGF)-1β in the serum. Uncontrolled hyperglycemia caused learning and memory impairments that corroborated degenerative changes, neuronal loss and expression of caspase (Casp)-3 in the hippocampal area of STZ-diabetic rats. Behavioral deficits were associated by decreased hippocampal glutamate (GLU), glycine, serotonin (5-HT) and dopamine. Moreover, diabetic rats showed an increase in hippocampal nitric oxide and thiobarbituric acid reactive substances versus decreased non-protein sulfhydryls. Though CBL did not affect STZ-induced hyperglycemia, it partly improved body weight as well as HbA1c%. Such effects were associated by enhancement in both learning and memory as well as apparent normal cellularity in CA1and CA3 areas and reduced Casp-3 expression. CBL improved serum TNF-α and IGF-1β, GLU and 5-HT as well as hampering oxidative biomarkers.

  • In conclusion, CBL possesses neuroprotection against diabetes-associated cerebral neurodegeneration and cognitive decline via anti-inflammatory, antioxidant and antiapototic effects.

 

 

Synapse. 2014 Jan;68(1):31-8. doi: 10.1002/syn.21718. Epub 2013 Oct 24.

Chronic cerebrolysin administration attenuates neuronal abnormalities in the basolateral amygdala induced by neonatal ventral hippocampus lesion in the rat.

Vázquez-Roque RA1, Ubhi K, Masliah E, Flores G.

Author information

  • 1Laboratorio de Neuropsiquiatría, Instituto de Fisiología, Universidad Autónoma de Puebla, 14 Sur 6301, CP, 72570, Puebla, México.

Abstract

The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior in the rat. Our previous report demonstrated that cerebrolysin (Cbl), a neuropeptide preparation which mimics the action of endogenous neurotrophic factors on brain protection and repair, promoted recovery of dendritic and neuronal damage of the prefrontal cortex and nucleus accumbens and behavioral improvements in postpubertal nVHL rats.

We recently demonstrated that nVHL animals exhibit dendritic atrophy and spine loss in the basolateral amygdala (BLA). This study aimed to determine whether Cbl treatment was capable of reducing BLA neuronal alterations observed in nVHL rats. The morphological evaluation included examination of dendrites using the Golgi-Cox procedure and stereology to quantify the total cell number in BLA. Golgi-Cox staining revealed that nVHL induced dendritic retraction and spine loss in BLA pyramidal neurons. Stereological analysis demonstrated nVHL also produced a reduction in cells in BLA. Interestingly, repeated Cbl treatment ameliorated dendritic pathology and neuronal loss in the BLA of the nVHL rats. Our data show that Cbl may foster recovery of BLA damage in postpubertal nVHL rats and suggests that the use of neurotrophic agents for the management of some schizophrenia-related symptoms may present an alternative therapeutic pathway in these disorders.

 

Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(3 vypusk 2 Insul't):43-50.

[Mechanisms of neurotrophic and neuroprotective effects of cerebrolysin in cerebral ischemia.]

[Article in Russian]

Gromova OA1, Torshin II, Gogoleva IV.

Author information

  • 1GBOU VPO "Ivanovskaia gosudarstvennaia meditsinskaia akademiia", Ivanovo.

Abstract

Cerebrolysin is the drug which contains peptides derived from the brain of a pig. It is used in neurological practice for recovery of stroke patients and treatment of dementia. Despite the evidence-basis and some experimental studies, the distinct mechanisms of pharmacological action of this drug remain unclear for most neurologists. In this paper, we present results of a molecular-biological analysis of peptide content of cerebrolysin. We have demonstrated the presence of active peptide fragments of nerve growth factor, enkephalins, orexin, halanin. The results of current clinical and experimental studies of cerebrolysin have been compared. The activity of above-mentioned neuropeptides explain experimental and clinical details of all known effects (neurotrophic, neuroprotective and immunomodulating) of cerebrolysin in ischemic and neurodegenerative CNS injuries. The analysis allowed to make conclusions about mechanisms of cerebrolysin action that were important for increasing the efficacy of this drug in clinical practice.

 

J Neurol Sci. 2014 Feb 15;337(1-2):104-11. doi: 10.1016/j.jns.2013.11.028. Epub 2013 Nov 26.

Cerebrolysin reduces amyloid-β deposits, apoptosis and autophagy in the thalamus and improves functional recovery after cortical infarction.

Xing S1, Zhang J1, Dang C1, Liu G1, Zhang Y2, Li J1, Fan Y1, Pei Z1, Zeng J3.

Author information

  • 1Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China.

  • 2Department of Neurology, The First Affiliated Hospital, Jinan University, No. 613 Huangpu Avenue West, Guangzhou 510630, China.

  • 3Department of Neurology and Stroke Center, The First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China. Electronic address: zengjs@pub.guangzhou.gd.cn.

Abstract

Focal cerebral infarction causes amyloid-β (Aβ) deposits and secondary thalamic neuronal degeneration. The present study aimed to determine the protective effects of Cerebrolysin on Aβ deposits and secondary neuronal damage in thalamus after cerebral infarction. At 24h after distal middle cerebral artery occlusion (MCAO), Cerebrolysin (5 ml/kg) or saline as control was once daily administered for consecutive 13 days by intraperitoneal injection. Sensory function and secondary thalamic damage were assessed with adhesive-removal test, Nissl staining and immunofluorescence at 14 days after MCAO. Aβ deposits, activity of β-site amyloid precursor protein-cleaving enzyme 1 (BACE1), apoptosis and autophagy were determined by TUNEL staining, immunofluorescence and immunoblot.

The results showed that Cerebrolysin significantly improved sensory deficit compared to controls (p<0.05).

  • Aβ deposits and BACE1 were obviously reduced by Cerebrolysin, which was accompanied by decreases in neuronal loss and astroglial activation compared to controls (all p < 0.05). Coincidently, Cerebrolysin markedly inhibited cleaved caspase-3, conversion of LC3-II, downregulation of Bcl-2 and upregulation of Bax in the ipsilateral thalamus compared to controls (all p<0.05).

  • These findings suggest that Cerebrolysin reduces Aβ deposits, apoptosis and autophagy in the ipsilateral thalamus, which may be associated with amelioration of secondary thalamic damage and functional recovery after cerebral infarction.

 

J Nanosci Nanotechnol. 2014 Jan;14(1):577-95.

The role of functionalized magnetic iron oxide nanoparticles in the central nervous system injury and repair: new potentials for neuroprotection with Cerebrolysin therapy.

Sharma HS, Menon PK, Lafuente JV, Aguilar ZP, Wang YA, Muresanu DF, Mössler H, Patnaik R, Sharma A.

Abstract

Functionalized Magnetic Iron Oxide Nanoparticles (FMIONPs) are being explored for the development of various biomedical applications, e.g., cancer chemotherapy and/or several other radiological or diagnostic purposes. However, the effects of these NPs per se on the central nervous system (CNS) injury or repair are not well known. This review deals with different aspects of FMIONPs in relation to brain function based on the current literature as well as our own investigation in animal models of CNS injuries. It appears that FMIONPs are innocuous when administered intravenously within the CNS under normal conditions.

However, abnormal reactions to FMIONPs in the brain or spinal cord could be seen if they are combined with CNS injuries e.g., hyperthermia or traumatic insults to the brain or spinal cord. Thus, administration of FMIONPs in vivo following whole body hyperthermia (WBH) or a focal spinal cord injury (SCI) exacerbates cellular damage. Since FMIONPs could help in diagnostic purposes or enhance the biological effects of radiotherapy/chemotherapy it is likely that these NPs may have some adverse reaction as well under disease condition.

Thus, under such situation, adjuvant therapy e.g., Cerebrolysin (Ever NeuroPharma, Austria), a suitable combination of several neurotrophic factors and active peptide fragments are the need of the hour to contain such cellular damages caused by the FMIONPs in vivo. Our observations show that co-administration of Cerebrolysin prevents the FMIONPs induced pathologies associated with CNS injuries. These observations support the idea that FMIONPs are safe for the CNS in disease conditions when co-administered with cerebrolysin. This indicates that cerebrolysin could be used as an adjunct therapy to prevent cellular damages in disease conditions where the use of FMIONPs is required for better efficacy e.g., cancer treatment.

 

Hum Exp Toxicol. 2014 Feb 24. [Epub ahead of print]

Do adipose tissue-derived mesenchymal stem cells ameliorate Parkinson's disease in rat model?

Ahmed H1, Salem A, Atta H, Ghazy M, Aglan H.

Author information

  • 11Department of Hormones, Medical Research Division, National Research Centre, Cairo, Egypt.

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder in middle-aged and elderly people. This study aimed to elucidate the role of mesenchymal stem cells (MSCs) in management of PD in ovariectomized rat model. MSCs were excised from adipose tissue of both the omentum and the inguinal fat pad of male rats, grown, and propagated in culture; then characterized morphologically; and by the detection of surface markers gene expression. In this study, 40 ovariectomized animals were classified into 5 groups; group 1 was ovariectomized control, groups 2 to 5 were subcutaneously administered with rotenone for 14 days after 1 month of ovariectomy for induction of PD.

Group 2 was left untreated; groups 3, 4, and 5 were treated with Sinemet®, Cerebrolysin®, and a single dose of adipose tissue-derived MSCs (ADMSCs), respectively. Y-chromosome gene (sry) was assessed by polymerase chain reaction (PCR) in brain tissue of the female rats. Serum transforming growth factor β (TGF-β), monocyte chemoattractant protein 1 (MCP-1), and brain-derived neurotrophic factor (BDNF) levels were assayed using enzyme-linked immunosorbent assay technique. Brain dopamine level was assayed fluorometrically, while brain tyrosine hydroxylase (TH) gene expression was detected by semiquantitative real-time PCR. The PD group showed significant increase in serum TGF-β and MCP-1 levels associated with significant decrease in serum BDNF, brain dopamine, and brain TH gene expression levels. In contrast, all treatments produce significant decrease in serum TGF-β and MCP-1 levels in concomitant with significant increase in serum BDNF, brain dopamine, and brain TH gene expression levels. In conclusion, the observed improvements in the studied biomarkers due to ADMSCs infusion might be attributed to their immunomodulatory, anti-inflammatory, and neurotrophic effects.

 

Br J Neurosurg. 2013 Dec;27(6):803-7. doi: 10.3109/02688697.2013.793287. Epub 2013 May 8.

Cerebrolysin enhances cognitive recovery of mild traumatic brain injury patients: double-blind, placebo-controlled, randomized study.

Chen CC1, Wei ST, Tsaia SC, Chen XX, Cho DY.

Author information

  • 1Department of Neurosurgery, China Medical University Hospital , Taichung , Taiwan.

Abstract

In adults, mild traumatic brain injury (MTBI) frequently results in impairments of cognitive functions which would lead to psychological consequences in the future. Cerebrolysin is a nootropic drug, and can significantly improve cognitive function in patients with Alzheimer's disease and stroke.

The purpose of this study was to investigate how Cerebrolysin therapy enhances cognitive recovery for mild traumatic brain injury patients using a double-blinded, placebo-controlled, randomized phase II pilot study. Patients having head injury within 24 h sent to our hospital were screened and recruited if patients were alert and conscious, and had intracranial contusion haemorrhage. From July 2009 to June 2010, totally, thirty-two patients were recruited in the double-blinded, placebo-controlled, and randomized study.

Patients were randomized to receive Cerebrolysin (Group A, once daily intravenous infusion of 30 mL Cerebrolysin over a 60-min period for 5 days) or placebo (Group B, same dosage and administration of normal saline as Group A). The primary outcome measures were differences of cognitive function including Mini-Mental Status Examination (MMSE), and Cognitive Abilities Screening Instrument (CASI) scores between baseline and week 1, between baseline and week 4, and between baseline and week 12. Thirty-two patients completed the trial. For Group A, the CASI score difference between baseline and week 12 was 21.0 ± 20.4, a significantly greater change than that of Group B (7.6 ± 12.1) (p = 0.0461). Besides, drawing function (one of the domains of CASI; p = 0.0066) on week 4 and both drawing function (p = 0.0472) and long-term memory (one of the domains of CASI; p = 0.0256) on week 12 were also found to be significantly improved in the patients receiving Cerebrolysin treatment.

  • Our results suggest that Cerebrolysin improves the cognitive function of the MTBI in patients at 3rd month after injury, especially for long-term memory and drawing function.

Zh Nevrol Psikhiatr Im S S Korsakova. 2013;113(12):76-80.

[The effect of cerebrolysin on the regeneration of the peripheral nerve depending on the scheme of paraneural administration].

[Article in Russian]

Shchudlo NA1, Shchudlo MM, Borisova IV.

Author information

  • 1FGBU Rossiĭskiĭ nauchnyĭ tsentr "Vosstanovitel'naia travmatologiia i ortopediia" im. akad. G.A. Ilizarova Minzdrava Rossii, Kurgan.

Abstract

An experimental morphological study in 56 animals has been performed in order to analyze the effect of cerebrolysin on the dynamics and long-term results of peripheral nerve regeneration after the transection and microsurgical suturing depending on the scheme of the preparation of paraneural infusion. The regeneration process was evaluated after 2.5; 4; 6 and 12 months. There was a stimulating effect of the preparation on the regenerative growth and differentiation of nerve fiber axial cylinders, vascularization of the distal segment of regenerating nerve and the trophic condition of myelin-forming Schwann cells. When the preparation is used according to the prolonged scheme, the effect persists for up to 10.5 months after the end of paraneural injection course.

The CAPTAIN Trial: Cerebrolysin Asian Pacific Trial in Acute Brain Injury and Neurorecovery May 2012

The purpose of this trial is to investigate safety and efficacy of Cerebrolysin as add-on therapy to standard care in patients with acute traumatic brain injury (TBI). The study duration for each patient is 180 days. Trial: IV infusion, 50 ml/day, 10 days (treatment cycle will be repeated one and two months later if patient has a score of less than 7 in the extended Glasgow Outcome Scale on Day 30)

Cerebrolysin in Vascular Dementia: Improvement of Clinical Outcome in a Randomized, Double-Blind, Placebo-Controlled Multicenter Trial

Journal of Stroke & Cerebrovascular Diseases, Volume 20, Issue 4, Pages 310-318, July 2011,

No drug to treat vascular dementia (VaD) has yet been approved by the American or European authorities, leaving a large population of patients without effective therapy. Cerebrolysin has a long record of safety and might be efficacious in this condition. We conducted a large, multicenter, double-blind, placebo-controlled study in 242 patients meeting the criteria for VaD. The primary endpoint was the combined outcome of cognition (based on Alzheimer's Disease Assessment Scale Cognitive Subpart, Extended Version [ADAS-cog+] score) and overall clinical functioning (based on Clinician's Interview-Based Impression of Change plus Caregiver Input [CIBIC+] score) assessed after 24 weeks of treatment. Intravenous Cerebrolysin 20 mL was administered once daily over the course of 2 treatment cycles as add-on therapy to basic treatment with acetylsalicylic acid. The addition of Cerebrolysin was associated with significant improvement in both primary parameters. At week 24, ADAS-cog+ score improved by 10.6 points in the Cerebrolysin group, compared with 4.4 points in the placebo group (least squares mean difference, −6.17; P < .0001 vs placebo). CIBIC+ showed a mean improvement of 2.84 in the treatment arm and 3.68 in the placebo arm, a treatment difference of 0.84 (P < .0001 vs placebo). These findings were confirmed by responder analyses demonstrating higher rates in the Cerebrolysin group (ADAS-cog+ improvement of ≥4 points from baseline, 82.1% vs 52.2%; CIBIC+ score of <4 at week 24, 75.3% vs 37.4%; combined response in ADAS-cog+ and CIBIC+, 67.5% vs 27.0%). For Cerebrolysin, the odds ratio for achieving a favorable CIBIC+ response was 5.08 (P < .05), and that for achieving a favorable combined response was 5.63 (P < .05). Our data indicate that the addition of Cerebrolysin significantly improved clinical outcome, and that the benefits persisted for at least 24 weeks. Cerebrolysin was safe and well tolerated.

Drugs Today (Barc). 2011 Jul;47(7):487-513.

Cerebrolysin in Alzheimer's disease

Antón Álvarez X, Fuentes P.

Source

EuroEspes Biomedical Research Centre, A Coruña, Spain. xantonal@yahoo.es

Abstract

Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on β-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 β intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.

Copyright 2011 Prous Science, S.A.U. or its licensors. All rights reserved.

 

Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals

Menon PK, Muresanu DF, Sharma A, Mössler H, Sharma HS.

Source

Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden.

Abstract

Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; Cerebrolysin is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins and the number of injured neurons. This indicates that cerebrolysin in higher doses could be a good candidate for treating SCI cases following nanoparticle intoxication. The possible mechanisms and functional significance of these findings are discussed in this review.

 

CNS Neurol Disord Drug Targets. 2012 Feb;11(1):7-25.

Superior neuroprotective effects of cerebrolysin in nanoparticle-induced exacerbation of hyperthermia-induced brain pathology

Sharma A, Muresanu DF, Mössler H, Sharma HS.

Source

Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, SE-75185 Uppsala, Sweden.

Abstract

In recent years, the incidence of heat stroke and associated brain pathology are increasing Worldwide. More than half of the world's population are living in areas associated with high environmental heat especially during the summer seasons. Thus, new research is needed using novel drug targets to achieve neuroprotection in heat-induced brain pathology. Previous research from our laboratory showed that the pathophysiology of brain injuries following heat stroke are exacerbated by chronic intoxication of engineered nanoparticles of small sizes (50-60 nm) following identical heat exposure in rats. Interestingly, in nanoparticle-intoxicated animals the known neuroprotective agents in standard doses failed to induce effective neuroprotection. This suggests that the dose-response of the drugs either requires modification or new therapeutic agents are needed to provide better neuroprotection in nanoparticle-intoxicated animals after heat stroke. This review is focused on the use of cerebrolysin, a mixture of several neurotrophic factors and active peptide fragments, in relation to other neuroprotective agents normally used to treat ischemic stroke in clinics in nanoparticle-induced exacerbation of brain damage in heat stroke. It appears that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal rats. Interestingly, to induce effective neuroprotection in nanoparticle-induced exacerbation of brain pathology a double dose of cerebrolysin is needed. On the other hand, double doses of the other drugs were quite ineffective in reducing brain damage. These observations suggest that the drug type and doses are important factors in attenuating nanoparticle-induced exacerbation of brain pathology in heat stroke. The functional significance and possible mechanisms of drug-induced neuroprotection in nanoparticle-treated, heat-stressed rats are discussed.

 

J Neural Transm Suppl. 2000;59:315-28.

Oral Cerebrolysin enhances brain alpha activity and improves cognitive performance in elderly control subjects.

Alvarez XA, Lombardi VR, Corzo L, Pérez P, Pichel V, Laredo M, Hernández A, Freixeiro F, Sampedro C, Lorenzo R, Alcaraz M, Windisch M, Cacabelos R.

Source

Department of Neuropharmacology, EuroEspes Biomedical Research Center, Santa Marta de Babío, Bergondo, A Corufia, Spain.

Abstract

Cerebrolysin is a porcine brain derived peptide preparation with potential neurotrophic activity. The effects of a single oral dose of the Cerebrolysin solution (30 ml) on brain bioelectrical activity and on cognitive performance were investigated in healthy elderly people. A single oral dose of Cerebrolysin induced a progressive increase in relative alpha activity power from 1 to 6 hours after treatment in almost all the brain electrodes in elderly control subjects. As compared with baseline alpha power (45.8+/-9.5%), the increase in relative alpha activity in the left occipital electrode (O1) reached significant values at 1 hour (57.2+/-8.5%; p < 0.05), 3 hours (59.4+/-7.6%; p < 0.05) and 6 hours (63.4+/-9.8%; p < 0.05) after Cerebrolysin administration. Enhancement in relative alpha power was accompanied by a generalized decrease in slow delta activity that was maximum at 6 hours after Cerebrolysin intake. A significant improvement in memory performance, evaluated with items of the ADAS cog, was also found in elderly people taken a single dose of oral Cerebrolysin (6.9+/-1.0 errors at baseline versus 4.9+/-1.0 errors after treatment; p < 0.01). This memory improvement was more evident in recognition (2.8+/-0.6 errors vs. 1.5+/-0.7 errors; p < 0.05) than in recall tasks (4.1+/-0.5 errors versus 3.4+/-0.5 errors; ns). These data indicate that Cerebrolysin potentiates brain alpha activity, reduces slow EEG delta frequencies and improves memory performance in healthy elderly humans, suggesting that this compound activates cerebral mechanisms related to attention and memory processes. According to the present results, it seems that oral Cerebrolysin might be useful for the treatment of memory impairment and brain damage in eldely subjects with or without neurodegenerative disorders.

 

Cerebrolysin in Patients With Acute Ischemic Stroke in Asia

Results of a Double-Blind, Placebo-Controlled Randomized Trial

Abstract

Background and Purpose: Cerebrolysin showed neuroprotective and neurotrophic properties in various preclinical models of ischemia and small clinical trials. The aim of this large double-blind, placebo-controlled randomized clinical trial was to test its efficacy and safety in patients with acute ischemic stroke.

Methods - Patients with acute ischemic hemispheric stroke were randomized within 12 hours of symptoms onset to active treatment (30 mL Cerebrolysin daily) or placebo (saline solution) given as intravenous infusion for 10 days in addition to aspirin (100 mg daily). The patients were followed up to 90 days. The primary end point was the result of a combined global directional test of modified Rankin Scale, Barthel Index, and National Institutes of Health Stroke Scale. Adverse events were documented to assess safety.

Results - A total of 1070 patients were enrolled in this study. Five hundred twenty-nine patients were assigned to Cerebrolysin and 541 to placebo. The confirmatory end point showed no significant difference between the treatment groups. When stratified by severity however, a post hoc analysis of National Institutes of Health Stroke Scale and modified Rankin Scale showed a trend in favor of Cerebrolysin in patients with National Institutes of Health Stroke Scale >12 (National Institutes of Health Stroke Scale: OR, 1.27; CI lower bound, 0.97; modified Rankin Scale: OR, 1.27; CI lower bound, 0.90). In this subgroup, the cumulative mortality by 90 days was 20.2% in the placebo and 10.5% in the Cerebrolysin group (hazard ratio, 1.9661; CI lower bound, 1.0013).

Conclusions - In this study, the confirmatory end point showed neutral results between the treatment groups. However, a favorable outcome trend was seen in the severely affected patients with ischemic stroke treated with Cerebrolysin. This observation should be confirmed by a further clinical trial.

 

J Neural Transm Suppl. 1998;53:385-98.

Dose-dependent effects of Cerebrolysin on EEG and short-term memory of healthy volunteers during control and hyperventilation induced cerebral ischemia

Funke M, Fiehler J, Mewes I, Eiselt M, Rother I, Windisch M.

Source

Institut of Pathological Physiology, Friedrich-Schiller-University, Jena, Federal Republic of Germany.

Abstract

Cerebrolysin, a peptidergic nootropic drug, was to be effective on learning and other cognitive functions in animal experiments as well as in clinical studies. Hyperventilation (HV) as a model of brain ischemia induces slowing of the EEG and cognitive impairment. The aim of this study was to examine the potential dose-dependent effects of Cerebrolysin on HV related EEG changes and short term memory during chronic (10 days) application and the time dependency of these effects. In this single centre, double blind, randomized, placebo-controlled, parallel group study 48 healthy males were enrolled and received either 100 ml placebo (NaCl) or Cerebrolysin (10 ml or 30 ml or 50 ml) in a volume of 100 ml (NaCl) for 10 days. EEG at baseline and during HV as well as the cognitive performance was evaluated at Day 1 (baseline, 15 min p.i., 2 h p.i., 4 h p.i., 8 h p.i., 24 h p.i.), Day 10 (baseline, 15 min p.i., 2 h p.i.,) and at day 11 (24 h. after the last infusion). The main effects found during the study can be summarized as follows: At baseline we found an increase of the EEG power ratio (PR) for the grouptrated with 10 ml Cerebrolysin. The effect was most pronounced at the parietal cortex. The effect started after 15 min, was most expressed at 2 h and was kept until 8 h. During HV we found a relative PR decrease of the group (10 ml Cerebrolysin) at 2 hours. For short term memory, there is a trend towards less effective word recall for the baseline situation during the first 4 hours for the placebo. This effect was not observed in the Cerebrolysin treated groups. If chronic effects are concerned, the PR increased over the parietal regions at 24 h for the groups treated with 10 and 30 ml Cerebrolysin. The effect remains at day 10 and 11. But at 10 and 11 days there was also a trend for a relative increase of the PR in the group treated with 50ml Cerebrolysin. Signs of overdosage occurred with the highest concentrations of Cerebrolysin. The events were only mild and caused no harm to the volunteers. The highest concentration caused a small but significant reduction of blood pressure. The effects could be interpreted as those of an atypical nootropic with anti-ischemic properties.