EP0624094A1 - Utilisation de facteurs de croissance des fibroblastes comme agents neuro-protecteurs et neuro-modulateurs - Google Patents

Utilisation de facteurs de croissance des fibroblastes comme agents neuro-protecteurs et neuro-modulateurs

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Publication number
EP0624094A1
EP0624094A1 EP94901818A EP94901818A EP0624094A1 EP 0624094 A1 EP0624094 A1 EP 0624094A1 EP 94901818 A EP94901818 A EP 94901818A EP 94901818 A EP94901818 A EP 94901818A EP 0624094 A1 EP0624094 A1 EP 0624094A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
fibroblast growth
acidic
aggressiveness
agitation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94901818A
Other languages
German (de)
English (en)
Inventor
Guillermo Gim Nez Gallego
Pedro Cuevas S Nchez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Espana SA
Original Assignee
Boehringer Ingelheim Espana SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim Espana SA filed Critical Boehringer Ingelheim Espana SA
Publication of EP0624094A1 publication Critical patent/EP0624094A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the use of polypeptides belonging to the family of fibroblast growth factors (acidic and basic and the non-mitogenic form of acidic FGF), as well as their derivatives, as substances that protect the nervous tissue following episodes of transient cerebral ischaemia followed by reperfusion, as well as to their use as substances with a neu- s romodulatory effect on motor activity.
  • fibroblast growth factors acidic and basic and the non-mitogenic form of acidic FGF
  • fibroblast growth factor proteins The family of fibroblast growth factor proteins is better known as broad- spectrum mitogens for cells derived from the mesoderm and the neuroectoderm (Gimenez- Gallego G. et al, Science 1985; 320:1385; Thomas K.A. & Gimenez-Gallego G., Trends Biochem. Sci. 1986; 11:1).
  • non-mitogenic activities of basic and acidic fibroblast 0 growth factor have been described (Baird A. et al, Proc. Natl. Acad. Sci. USA 1985; 82:5545; Baird A. & Hsueh J., Regulatory Peptides. 1986; 16:243).
  • the central nervous system is very rich in fibroblast growth factors (Thomas A.
  • fibro- s blast growth factors are substances with neurotrophic capacity (Helti F., in: Clane D.B., Grippa D., Trabucchi M., Lon ⁇ G., Horowski R. (eds.), Parkinson and Aging. Raven Press Ltd. New York 1989: 79; Schawaber J.S. et al, J. Comp. Neurol. 1991; 309: 79), capable of maintaining the survival of nervous tissue and of inducing, when administered exoge- nously, the regeneration of damaged neurones.
  • fibroblast growth factors are capable of inducing the formation of new blood vessels (angiogenesis) under normal and pathological conditions (ischaemia) (Cuevas P. et al, in: Gagliari R., Benvenutti L. (eds.), Controversies in EIAB for cerebral ischemia. Monduzzi. Florence 1988; 731; Purimala M. et al, Brain Res. 1991, 558: 315), and of
  • EP 0 388 226 describes the use of aFGF for neuro- protection in an ischaemia reperfusion model wherein aFGF was injected into the brain lateral ventricles through a cannula connected to an Alzet's mini-pump.
  • EP 0 357 240 de ⁇ scribes the use of FGF for neuroprotection in an ischaemia/reperfusion model applying the drug intraperitoneally.
  • protection was significantly worse as compared to EGF, and no protection was observed at higher concentrations (1 mg/kg, 10 mg/kg). Further- more, FGF application started prior to the ischaemic event, while in most clinical cases the application of the drug will take place after such an event.
  • the subject of the present invention is the use of fibroblast growth factor, ana ⁇ logue proteins or compounds derived from the latter as intravenously administered neuro ⁇ protective substances in cases of cerebral ischaemia, especially when being transient and followed by reperfusion.
  • the application of the drug takes place after an ischaemic event has happened.
  • Adequate formulations of acidic and basic fibroblast growth factors and the mon-mitogenic form of acidic FGF can be used as neuroprotective medicinal products in all emergency clinical situations which require protection, e.g.
  • Hypothermic circulatory arrest used in pediatric cardiac surgery and procedures of the aortic arch and thoracic aorta, com- plex neurological operations, excision of renal cell carcinomas and ligation of large trauma ⁇ tic arteriovenous fistulas is accompanied with neurological sequelae when the period of circulatory arrest is extended beyond 1 hour (HCA-induced brain damage can occur in up to 4% of children (Tharion J. et al., J. Thorac. Cardiovasc. Surg. 1982, 88: 66-72) and 15% of adults (Davis E. A. et al., Ann. Thorac.
  • FGF FGF
  • analogue proteins or compounds derived from the latter can be used in these cases.
  • a further aspect of the present invention is the use of FGF as a pharmaceutical in cases of disturbed motor activity or aggressiveness.
  • the present invention extends to the use of fibroblast growth factor, analogue proteins or compounds derived from the latter, administered subcutaneously, in situations in which there is exagge ⁇ rated motor activity (hyperkinesia and motor agitation) as well as in situations of aggres- siveness.
  • This novel neuromodulatory activity of fibroblast growth factor has been analyzed in 200 rats.
  • compositions containing FGF can be used in all clinical situa ⁇ tions which require a decrease in agitation and aggressiveness, as occurs in: psychomotor agitation, infantile hyperkinetic syndrome, maniacal agitation, paranoid schizophrenia, alcoholic irritability, aggressiveness, of the advanced phases of dementia, epileptic aggres- siveness, abnormal hyperkinesia, acute confusional states, psychotic aggressiveness, and the like.
  • compositions inten ⁇ ded for use as neuroprotective or neuromodulatory agents as described are pharmaceutical compositions inten ⁇ ded for use as neuroprotective or neuromodulatory agents as described.
  • Figure 1 is a picture of a coronal section of the dorsal hippocampus of a gerbil subjected to cerebral ischaemia for 5 minutes followed by reperfusion for 7 days.
  • the animal received intravenously 50 ⁇ l of 0.1% heparin in PBS.
  • the rectangle in the figure delineates the sector of the CA1 area of the hippocampus in which the pyramidal cells were counted.
  • Figure 2 shows at higher magnification the delineated area of Figure 1, in which the disor ⁇ ganisation and neuronal necrosis can be appreciated.
  • Figure 3 presents a coronal section of the dorsal hippocampus of a gerbil subjected to cere ⁇ bral ischaemia for 5 minutes followed by a 7 day reperfusion that received intravenously 2.6 ⁇ g of aFGF, 20 seconds after the reperfusion onset.
  • the protein was injected in 50 ⁇ l of PBS containing 0.1% of heparin.
  • the rectangle in the figure delineates the sector of the CA1 area of the hippocampus in which the pyramidal cells were counted.
  • Figure 4 corresponds to an enlargement of the rectangle in Figure 3.
  • the preservation of the stratified appearance of the pyramidal neurons can be observed; there are only a few degenerate cells (arrow).
  • Figure 5 is a histogram of the average number of normal neurons counted in the CA1 area of the dorsal hippocampus of sham operated animals (normal in the figure) and those, FGF- treated and untreated, that suffered a brain ischaemia of 5 minutes ensued by a reperfusion of 7 days.
  • Figure 6 shows 3 histograms which reflect the effect of aFGF on horizontal, vertical and stereotyped motor behaviour. These three types of movement were analysed for 30 minutes after 30 minutes had elapsed following the subcutaneous injection of FGF at different con ⁇ centrations (1 ⁇ g/kg, 10 ⁇ g/kg and 100 ⁇ g/kg).
  • Figure 7 shows 3 histograms in which the effect of bFGF on the horizontal, vertical and stereotyped motor behaviour can be observed. Movement analyses and bFGF treatments were as in Figure 6.
  • Figure 8 presents autoradiographs of coronal sections of the CA1 areas of the dorsal hip ⁇ pocampi of rats which were sacrificed two hours after intravenous injection of 0.1 ⁇ g C 14 - aFGF.
  • A native C 14 -aFGF.
  • B heat-denatured C 14 -aFGF. Effective enrichment of native aFGF within the hippocampus can be appreciated, while heat-denatured aFGF fails to do so.
  • the FGF's used for the following experiments were prepared according to a previously published procedure (Gene 1992, 311: 231-238).
  • the 139 residues form of aFGF and the 146 one of bFGF were used.
  • the vasoactive non-mitogenic form of aFGF was prepared as described (Science 1991, 254: 1208-1210).
  • Example 1 Analysis of the neuroprotective effect of FGF in a cerebral ischaemia/reper ⁇ fusion model Thirty six gerbils of both sexes were employed. Their weight fluctuated between
  • the advantage of using this rodent consists in the property it possesses of ha ⁇ ving a fairly clearly demarcated vascular region arising from the vertebral arteries of the ar ⁇ terial region originating from the carotid arteries.
  • Anaesthesia was induced by an intraperi- toneal injection of 3 ml/kg of a solution of ketolar (2.5 mg/ml), atropine (0.1 mg/ml) and valium (2 mg/ml). Both common carotids were exposed and occluded for 5 minutes by means of a knot using a silk thread. Reperfusion is obtained by untying the knot.
  • Ten gerbils were sham operated by treating them in an identical form but without occluding both caro ⁇ tids. Twenty seconds after the reperfusion onset, 13 animals received intravenously (right external jugular vein) 2.6 ⁇ g of acidic fibroblast growth factor dissolved in phosphate-buf- fered saline solution (PBS) containing 0.1% of heparin. The volume of solution injected was 50 ⁇ l. Another 13 animals received 50 ⁇ l of 0.1% heparin/PBS twenty seconds after the reperfusion onset.
  • PBS phosphate-buf- fered saline solution
  • the animals were allowed to live for 7 days, being then perfused via the left heart ventricle for a histological evaluation of the normal neurons of the CA1 area of the dorsal hippocampus, a zone in which the ischaemic lesion is localised in this animal subjected to this period of ischaemia and reperfusion (Gill R. & Woodrriff G.N., Eur. J. Pharmacol. 1990; 176: 143).
  • the brains were isolated and immersed in 10% buffered formaldehyde solution for 3 days. They were then placed in a buffered solution containing 30% sucrose. The next day, the brains were frozen and serial sections (14 ⁇ ) were cut using a freezing microtome.
  • the frontal serial sections were stained alternately with haematoxylin/eosin and with cresyl violet. Sections were obtained between -1.4 and -2 mm from the bregma point. Those pyramidal neurons which possessed an apparent nucleus were considered to be normal. The degenerate cells exhibited an intense pyknosis and very irregular shape. Survival rate of pyramidal neurons after ischaemia and reperfusion in each
  • SUBSTITUTE SHEET animal was estimated in four randomly selected sections of the horizontal portion of the CA1 sector of each dorsal hippocampus, separated more than 200 ⁇ m from each other in order to avoid taking into account twice the same cell, by counting the normal pyramidal neurons in a defined area of 0.5 mm identically located in each section ( Figures 1 and 3).
  • Figures 1 and 3 The average number of surviving neurons counted in sham-operated animals and those sub ⁇ jected to 7 days of reperfusion after 5 minutes of ischaemia, either treated with aFGF or vehicle are summarized in Figure 5.
  • Example 2 Analysis of the neuromodulatory effect of FGF on motor activity
  • Adult male Wistar rats withing 200-250 g were used. They were housed in groups of 4-5 per cage and kept under controlled temperature and light-dark schedule (lights on between 07.00 and 19.00 H). The animals received food and water ad libitum. Appropriate and rigorous experimental control and maximal standardization of experimental procedure was followed.
  • This place constitutes a completely novel environment for the animals. It contains two perpendicular arrays of 15 horizontal infrared beams and two vertical light screens (infrared). Each interruption of the beam generates an electric impulse counted by an internal electronic counter. The horizontal activity, vertical activity and stereotypy counts displayed by the animals were selected for the purpose of this study.
  • Rats were injected subcutaneously with FGF (acidic or basic) or the appropriate vehicle (PBS containing 1% BSA and heparin) in a volume of 0,5 ml and immediately intro- prised in the activity cage for a 60 min session (testing time between 9.00 and 14.00 a.m.). The activity parameters were recorded every 5 min.
  • FGF acidic or basic
  • PBS containing 1% BSA and heparin
  • FIGS. 6 and 7 show the behavioral responses to the activity cage corresponding to the last 30 min of the total ses- sion, as reflected by the horizontal distance, vertical activity and stereotypy counts. Data are expressed as mean + SEM and significance is taken as P ⁇ 0.05.
  • systemic administration of either acidic FGF (aFGF) or basic (bFGF) to normal rats decreased locomotor activity with respect to animals injected with the vehicle, in a dose de-
  • Table I collates in a clear way the data demonstrating: i) that the behavior-modi ⁇ fying activity is specific to FGF since, when the preparation is hydrolysed by treatment with proteases, that preparation becomes inactive; ii) that the behavior modulating activity of the preparation depends on the spatial conformation of the protein since, when its three-dimen ⁇ sional structure is distorted by fusion with the c-terminus of the Streptococcus pneumoniae autolysin, this protein significantly loses its capacity of modifying the rat behavior, on spite of still being mitogenic and vasoactive; iii) that the capacity of FGF to modulate the activity of the animals does not depend on its mitogenic activity, since a form a FGF rendered non- mitogenic by protein engineering, significantly modifies the activity of the rats.
  • Example 3 Entrance aFGF into the brain Radioactive aFGF was produced by growing bacteria transformed with an aFGF expression vector in minimal medium with C 14 -glucose as carbon source. 0.1 ⁇ g of uniform ⁇ ly labeled C 14 -aFGF, either native or heat-denatured, were injected intravenously into wistar rats (250 g average weight). After two hours, the animals were sacrificed, the brain extrac ⁇ ted and cryosectioned, and the sections autoradiographed for one month. Figure 8 shows two autoradiographs demonstrating that native aFGF effectively enters into the brain.
  • aFGF-autolysin 120 ⁇ g/kg, purified by DEAE
  • aFGF-autolysin 40 ⁇ g/kg, purified by heparin
  • compositions containing acidic fibroblast growth factor injected intravenously immediately protect neuro ⁇ nal tissue against the damages following cerebral ischaemia and reperfusion.
  • FGF administered subcutaneously in the form of a single bolus significantly reduces the number of horizontal, vertical and stereotyped movements in rats living under normal conditions.
  • fibroblast growth factor is a potent neuroprotective agent follo ⁇ wing transient cerebral ischaemia and is likewise a neuromodulatory active agent producing motor hypoactivity.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Utilisation du facteur de croissance des fibroblastes et de ses dérivés comme agents protecteurs dirigés contre les lésions dues à l'ischémie et à la reperfusion cérébrale, et comme agents neuro-modulateurs de l'activité motrice, et de tous les composés associés, dans les cas cliniques exigeant une protection neuronale suivant l'ischémie cérébrale ou carotidienne. L'utilisation du facteur de croissance de fibroblastes acide ou basique et de tous les composés associés est également indiquée dans les cas cliniques exigeant une diminution de l'agitation et de l'agressivité.
EP94901818A 1992-11-23 1993-11-19 Utilisation de facteurs de croissance des fibroblastes comme agents neuro-protecteurs et neuro-modulateurs Withdrawn EP0624094A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ES09202360A ES2061380B1 (es) 1992-11-23 1992-11-23 Empleo del factor de crecimiento fibroblastico y sus derivados como neuroprotectores y neuromoduladores.
ES9202360 1992-11-23
PCT/EP1993/003234 WO1994012201A1 (fr) 1992-11-23 1993-11-19 Utilisation de facteurs de croissance des fibroblastes comme agents neuro-protecteurs et neuro-modulateurs

Publications (1)

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EP0624094A1 true EP0624094A1 (fr) 1994-11-17

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EP94901818A Withdrawn EP0624094A1 (fr) 1992-11-23 1993-11-19 Utilisation de facteurs de croissance des fibroblastes comme agents neuro-protecteurs et neuro-modulateurs

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EP (1) EP0624094A1 (fr)
JP (1) JPH07504205A (fr)
CA (1) CA2127537A1 (fr)
ES (1) ES2061380B1 (fr)
WO (1) WO1994012201A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5831117A (en) 1995-01-20 1998-11-03 G. D. Searle & Co. Method of preparing retroviral protease inhibitor intermediates
DE69634907T2 (de) * 1995-04-25 2006-05-18 Ajinomoto Co., Inc. Fibroblastenwachstumsfragmente
ES2201287T5 (es) * 1996-03-22 2007-10-16 Curis, Inc. Metodo para mejorar la recuperacion funcional de la coordinacion motora, del habla o la percepcion sensorial tras una isquemia o trauma del sistema nervioso central.
AU749530B2 (en) * 1997-06-11 2002-06-27 Acorda Therapeutics, Inc. CNS neuroregenerative compositions and methods of use
AU8855798A (en) * 1997-07-03 1999-01-25 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Novel composition for treating, preventing and/or delaying ischemic cell death
JP3507884B2 (ja) * 2000-03-07 2004-03-15 新潟大学長 遺伝子発現を指標とする統合失調症の客観的診断法
CA2571243A1 (fr) 2004-06-21 2006-01-05 The Board Of Trustees Of The Leland Stanford Junior University Genes et voies exprimes de maniere differentielle dans des troubles bipolaires et/ou troubles depressifs majeurs
EP1951908B1 (fr) 2005-11-12 2013-08-07 The Board of Trustees of The Leland Stanford Junior University Méthodes associées au fgf2 pour diagnostiquer et traiter une dépression

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5057494A (en) * 1988-08-03 1991-10-15 Ethicon, Inc. Method for preventing tissue damage after an ischemic episode
JP2814529B2 (ja) * 1989-03-16 1998-10-22 味の素株式会社 虚血性脳障害治療薬
WO1993008828A1 (fr) * 1991-11-08 1993-05-13 Syntex-Synergen Neuroscience Joint Venture Traitements de lesions neuronales liees a l'ischemie, a l'hypoxie ou a la degenerescence neuronale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9412201A1 *

Also Published As

Publication number Publication date
JPH07504205A (ja) 1995-05-11
ES2061380B1 (es) 1995-07-01
CA2127537A1 (fr) 1994-06-09
WO1994012201A1 (fr) 1994-06-09
ES2061380A1 (es) 1994-12-01

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