Mode of Action

TBI

DEMENTIA

Mode of Action

Reconnecting Neurons. Empowering for Life. NEW MULTI-MODAL THERAPIES FOR NEUROLOGICAL DISORDERS

Sonic hedgehog (Shh) The Sonic Hedgehog (Shh) signalling pathway regulates the development Smoothened of organs including the organization of the brain. For example, the Shh (Smo) Patched (Ptch) activates the Gli complex, which is responsible for the expression of develop- mental genes underpinning neurorecovery and leading to an amplification of natural recovery.

Gli Complex

Gli Repressor Gli Activator

Cerebrolysin activates the Shh pathway1

Cerebrolysin has a promoting effect on neurogenesis and oligodendrogenesis via stimulating the expression of the Shh signalling pathway. Cerebrolysin increases mRNA modulation of Shh and its receptors ‘Patched’ (Ptch) and ‘Smoothened’ (Smo).

Shh PTCH Smo 5 * * 3 * 3 4 (n=9) (n=9) *p<0.05 (n=9) *p<0.05 *p<0.05 3 2 2

2 1 1 Fold changes (mean±SE) changes Fold (mean±SE) changes Fold 1 (mean±SE) changes Fold

0 0 0 0 20 0 20 0 20 CERE (µl/ml) CERE (µl/ml) CERE (µl/ml)

Figure 1: Cerebrolysin stimulates the expression of the sonic hedgehog signalling pathway components in neural progenitor cells. Graphs show mRNA levels in an in vitro experiment.

Studies confirm the important role of the sonic hedgehog pathway in post-stroke brain repair and functional recovery, and suggests the Shh pathway to be a possible target for prolongation of the therapeutic window after stroke.2 MAINTENANCE AND RECOVERY OF THE NEURONAL NETWORK

Neurotrophic factors (NTFs) are signaling molecules that maintain, protect, and restore the neuronal network and ensure proper functioning of the brain. An important role of NTFs are in the survival and regeneration of the neuronal network upon stroke, traumatic brain injury or in chronic diseases is well-documented.

Cerebrolysin mimics activities of NTFs3 3

2.5 Cerebrolysin is a neuropeptide preparation that acts like 2 neurotrophic factors. Several fragments of NTFs have been identified in Cerebrolysin by immunoassay (ELISA) which 1.5 OD 405

are capable of stimulating neurotrophic signaling pathways. 1

0.5 CNTF Ciliary Neurotrophic Factor GDNF Glial Cell Line Derived Neurotrophic Factor 0 IGF1 Insulin-like Growth Factor 1 0.01 0.1 1 10 100 1000 10000 IGF2 Insulin-like Growth Factor 2 CL (nmole Peptides) Figure 2: Fragments of NTFs in Cerebrolysin

4 Cerebrolysin modulates NTFs BDNF proBDNF TRKB Ca2+ 6 7

Cerebrolysin shows BDNF-like activity by Extracellular Astrocyte 5 processing by stimulation of the PI3K/Akt pathway, which MMPs or plasmin 5 p75NTR Sortilin CDK5 SORCS2 plays an important role in cell growth, proli- P P RAC ↑ RHO feration, differentiation and migration. FRS2 SHC PLCγ1 TIAM1 ↓ RAC JNK SOS GRB2 PAK Caspase 3 RAS GAB1 IP3 DAG Actin dynamics Apoptosis RAF PI3K Ca2+ PKC

MEK1/2 AKT CAMK C CERE LY Postsynaptic Apoptosis ERK1/2

pAKT CYFIP1 mTOR CREB Growth FMRP cone retraction Protein Gene AKT translation expression

Neuronal survival, di erentiation and Figure 3: Cerebrolysin-dependent activation synaptic plasticity of AKT kinase.

Cerebrolysin is a multi-modal neuropeptide drug which improves the brain’s ability for self-repair by stimulating neurorecovery A MULTI-MODAL DRUG FOR ACUTE AND POST-ACUTE NEUROLOGICAL DISORDERS

MOTOR AND NEURO NEURO Phase COGNITIVE PROTECTION RECOVERY IMPROVEMENT

Neurotrophic support Mediators Regeneration Pathways (Sonic hedgehog – Shh)

Protection against excitotoxicity

Reduction of free radicals

Reduction of Pharmacological pro-apoptotic enzymes Effects Modulation of inflammatory response

Neuroplasticity

Neurogenesis

1 ZHANG, li, et al. Sonic hedgehog signaling pathway mediates cerebrolysin-improved neurological function after stroke. Stroke, 2013, 44. Jg., nr. 7, S. 1965 – 1972. 2 JIN, Yongming, et al. Poststroke sonic hedgehog agonist treatment improves functional recovery by enhancing neurogenesis and angiogenesis. Stroke, 2017, 48. Jg., nr. 6, S. 1636 – 1645. 3 CHEN, Honghui, et al. Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis. Neurobiology of aging, 2007, 28. Jg., nr. 8, S. 1148 – 1162. 4 ZHANG, Chunling, et al. Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. Journal of neuroscience research, 2010, 88. Jg., nr. 15, S. 3275 – 3281.

Copyright © 2018 by EVER Neuro Pharma GmbH, Oberburgau 3, 4866 Unterach, Austria. All rights reserved. No part of this brochure may be reproduced in any form or by any electronic or mechanical means, including information storage and retrieval systems, without permission in writing from the publisher. Cerebrolysin is a registered trademark of EVER Neuro Pharma GmbH, 4866 Unterach, Austria.

ABBREVIATED PRESCRIBING INFORMATION - Cerebrolysin Name of the medicinal product: Cerebrolysin® - Solution for injection. Qualitative and quantitative composition: One ml contains 215.2 mg of porcine brain-derived peptide preparation (Cerebrolysin® concentrate) in aqueous solution. List of excipients: Sodium hydroxide and water for injection. Therapeutic indications: Organic, me- tabolic and neurodegenerative disorders of the brain, especially senile dementia of Alzheimer‘s type - Post-apoplectic complications - Craniocerebral trauma; post-ope- rative trauma, cerebral contusion or concussion. Contraindications: Hypersensitivity to one of the components of the drug, epilepsy, severe renal impairment. Marketing Authorisation Holder: EVER Neuro Pharma GmbH, A-4866 Unterach. Only available on prescription and in pharmacies. More information about pharmaceutical form, posology and method of administration, special warnings and precautions for use, interaction with other medicinal products and other forms of interaction, fertility, pregnancy and lactation, effects on ability to drive and use machines, undesirable effects, overdose, pharmacodynamics properties, pharmacokinetic properties, precli- nical safety data, incompatibilities, shelf life, special precautions for storage, nature and contents of the container and special precautions for disposal is available in the summary of product characteristics. (Reference SPC – CCDS Version 1.0/Jan 28 2014)

EVER Neuro Pharma GmbH Oberburgau 3 4866 Unterach Austria