WO1998020864A9 - Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives - Google Patents

Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives

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Publication number
WO1998020864A9
WO1998020864A9 PCT/EP1997/006323 EP9706323W WO9820864A9 WO 1998020864 A9 WO1998020864 A9 WO 1998020864A9 EP 9706323 W EP9706323 W EP 9706323W WO 9820864 A9 WO9820864 A9 WO 9820864A9
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WO
WIPO (PCT)
Prior art keywords
prevention
treatment
salicylate
group
acid
Prior art date
Application number
PCT/EP1997/006323
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English (en)
Other versions
WO1998020864A3 (fr
WO1998020864A2 (fr
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Publication date
Priority claimed from IT96MI002356A external-priority patent/ITMI962356A1/it
Application filed filed Critical
Publication of WO1998020864A2 publication Critical patent/WO1998020864A2/fr
Publication of WO1998020864A9 publication Critical patent/WO1998020864A9/fr
Publication of WO1998020864A3 publication Critical patent/WO1998020864A3/fr

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Definitions

  • the present invention relates to the use of selected non-steroidal antinflammatory compounds for the prevention and the treatment of glutamate receptor- mediated neuronal damages, such compounds being selected from:
  • A is H; ( C1-C4 )-alkyl , optionally substituted with a carboxyl group; ( C3-C4 )-alkenyl or alkynyl; phenyl optionally substituted with a carboxyl group; naphthyl; COR, SO3R; B is OR 1 ; NHR 2 ;
  • R is (C 1 -C4)-alkyl
  • R 1 is H; an ammonium cation; a pharmaceutically acceptable cation of an alkali or alkaline-earth metal or of an organic base; ( C1C4 )-alkyl , optionally substituted with a hydroxyl or phenoxyl group, which can in its turn
  • X is OH; NH2; phenyl optionally substituted with one or more fluorine atoms; 4 , 5dihydro-2-phenyl-3H-benzindol-3- yl; p-aminobenzenesulfonamido; 4- [ ( pyridinylamino ) sulfo- nyl]phenyl-;
  • Y is H; OH; and the pharmaceutically acceptable salts and metabolites thereof;
  • Examples of cations deriving from pharmaceutically acceptable organic bases are aliphatic organic amines, such as glucamine, cyclic amines, such as morpholine, heterocyclic amines such as imidazole, and those deriving from amino acids, such as lysine.
  • the compounds of general formula (I) comprise medicaments having antiinflammatory and/or analgesic and/or antipyretic activities (NSAID) selected from the group consisting of acetylsalicylic acid (ASA), sodiurtr salicylate (NaSal), salicylamide , salicylamide- Oacetic acid, salacetamide , flufenisal, diflunisal, aceta ino- salol, calcium acetylsalicylate , benorylate, fendosal, salicyl-sulforic acid, etersalate, gentisic acid, glycol salicylate, mesalamine, imidazole salicylate, lysine acetylsalicylate, morpholine salicylate, 1-naphthyl salicylate, parsalmide, phenyl acetylsalicylate, salsa- late, sulfasalazine , olsala
  • a preferred embodiment of the present invention provides the use of ASA or of its metabolite, NaSal, for the prevention and/or the treatment of glutamate receptor-mediated neuronal damages.
  • ASA is undoubtedly the most widely employed medicament among NSAIDs, thanks to it its very wide pharmacological spectrum which makes ASA suitable, at different dosages, as an analgesic, antinflammatory and antipyretic agent and for limiting the risk of cardiac diseases as well as episodic ischemic syndromes; recently the lower incidence of lung, colon and breast cancer following the repeated administration of ASA has been proved.
  • AD Alzheimer' disease
  • Glutamate is the most abundant excitatory neurotransmitter in the brain. However, under certain undefined conditions, it may become a potent excitotoxin. Its contribution to the neurodegeneration associated with several acute and chronic neurodegenerative disorders, including AD, is widely established [Lipton et al,, New Engl. J. Med. 330, 613-622 (1995); M. Memo et al . , Int. Rev. Psych. 7, 339 (1995)].
  • NMDA N- methyl-D-aspartate
  • acetylsalicylic acid ASA
  • NaSal sodium salicylate
  • salicylic acid salicylamide, salicy amide-O-acetic acid and salacetamide
  • those ASA and NaSal derivatives having bioavailability characteristics at the brain level.
  • non-steroidal antiinflammatory compounds are particularly suitable for use in the prevention of glutamate receptor-mediated neuronal damages related to Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson' disease, cranial and spinal traumas, multi- infarct dementia, Lewy Body dementia, AIDS-associated dementia, central and peripheral ischemic neuropathies, neuropathies due to anoxic and/or glyce ic damages, multiple sclerosis, infective and/or toxic neurodegenerative diseases, neurodegenerative syndromes in prion diseases, ataxias-telangiectasias , epilepsy- related neurodegenerative processes, metabolic neuropathies and other related neuropathologies .
  • a further object of the present invention is the use of non-steroidal antiinflammatory compounds for the preparation of a medicament for the prevention and/or the treatment of glutamate receptor-mediated neuronal damages .
  • ASA and NaSal were added to the culture medium 5 min before the addition of glutamate.
  • Glutamate was used at a 50 ⁇ M concentration, which concentration is * capable of reducing cell survival by 70-80 % .
  • the range of the concentrations used for both drugs is related, as it is shown in the following table, to the plasma levels reached during the antiinflammatory therapy of patients affected with rheumatic diseases.
  • a dose-dependent protection against glutamate-induced neurotoxicity was observed in the presence of both drugs.
  • the calculated value i.e. the mean effective concentration inducing a 50% effective response (hereinafter referred to as EC5 0 ) was 1.7 M, with a maximum effect (equivalent to 83% protection) exerted at 3 M.
  • the concentration of NaSal giving 50% of protection was about 5 mM, with a maximal response (87% protection) observed at 10 M.
  • indomethacin was unable to prevent glutamate-evoked cell death at doses compatible with the plasma levels during drug chronic treatment, (1- 20 mM) (Table 1) .
  • hippocampus contains the neurons which are the most vulnerable to excitotoxic damage, namely the granular and pyramidal; additionally, the ex vivo preparation represents an heterogeneous population of neurons which have been differentiated in vivo .
  • stimulation of the NMDA receptor subtype by application of the selective agonist specifically induced a characteristic cell injury.
  • ASA effect of ASA was evaluated at concentrations ranging from 1 to 10 mM.
  • a quantitative analysis of the results is summarized in Fig. 2.
  • ASA did not modify cell viability at 1 mM concentration, while at 3 mM it specifically produced a significant neuroprotection in the CA3 region.
  • Higher concentrations of ASA elicited an almost complete prevention of NMDA effect even in CA1 and DG, besides CA3.
  • the drug did not modify per se neuron viability.
  • Cytosolic free calcium concentration was investigated in single cells by microfluorimetric technique using the fluorescent probe "Fura 2" (from Sigma) as described by M. Pizzi et al. in Mol. Pharmacol. 49, 586 (1996).
  • Cells were exposed to glutamate for 2 min in the chamber containing Mg 2+ -free Krebs-Ringer solution (KRS).
  • KRS Mg 2+ -free Krebs-Ringer solution
  • ASA and/or NaSal were added to the chamber 2 min before glutamate exposure. Fluorescence image acquisition and analysis were performed by MIRAcal (Multiple Image Rationing and Analysis with Calibration) system by Applied Imaging (UK).
  • ASA applied at neuroprotective concentrations ranging from 1 to 3 M, induced no changes in cell responsiveness to glutamate. It should be noted that the drug induced per se an exceedingly limited and transient increase in calcium concentration.
  • FIG. 3B A representative experiment performed utilizing 3 M ASA is depicted in Fig. 3B.
  • rat cerebellar granule cells also results in upregulation of the NF-kB nuclear activity and of the transcriptional complex AP-1 (Fig.4).
  • Cells were exposed to 50 ⁇ M glutamate in the absence or presence of ASA (1, 3 mM) and NaSal (3, 10 M) and nuclear extracts were prepared 1 h after stimulation.
  • Nuclear extracts from rat cerebellar granule cells were subjected to an electrophoretic mobility-shift assay with ⁇ - 32 P-labeled oligonucleotide probes containing the im unoglobulin kB (lanes 1 to 6 ) and the AP-1 DNA binding sites (lanes 7 to 12).
  • Cells were either unstimulated (lanes 1 and 7) or stimulated with 50 ⁇ M glutamate (15-min pulse) in the absence (lines 2 and 8) or presence (lanes 3 to 6 and 9 to 12) of the drugs as indicated. Both drugs inhibited glutamate-induced increase of NF-kB activity in a concentration-dependent manner (Fig.4), with calculated EC50 values of 1.3 M and 6 mM for ASA and NaSal respectively.
  • ASA and NaSal failed to modify the glutamate-mediated nuclear induction of the transcriptional complex AP-1 (Fig. 4). Therefore it is ascertained that, at concentrations " compatible with plasma levels reached during treatment of chronic inflammatory states, salicylates prevent glutamate-induced neurotoxicity .
  • the site of action common to ASA and NaSal, but not to indo ethacin is the blockade of induction of NF-kB transcription nuclear factors, which is a indisputable prove of the relationship between neuroprotection and cellular event.
  • the results were obtained preparing primary cultures of cerebellar granule cells from cerebella of 8-day-old rats ( Sprague-Dawley) .
  • the cultures were used at 10-12 days in vitro (DIV), and contained > 95% glutamatergic granule neurons.
  • Neurotoxicity was induced essentially as follows: cells were washed twice with Mg 2+ -free Locke solution [154 M NaCl; 5.6 mM KCl; 3.6 mM NaHC0 3 ; 2.3 mM CaCl2; 5.6 mM glucose; 5 mM HEPES (buffer solution base on N-[2-hydroxyethyl]-piperazin-N' -ethanesul onic acid) free from magnesium ions and afterwards were incubated with 50 ⁇ M glutamate in Locke solution free from magnesium ions for 15 minutes (25°C).
  • Mg 2+ -free Locke solution [154 M NaCl; 5.6 mM KCl; 3.6 mM NaHC0 3 ; 2.3 mM CaCl2; 5.6 mM glucose; 5 mM HEPES (buffer solution base on N-[2-hydroxyethyl]-piperazin-N' -ethanesul onic acid) free from magnesium ions and afterwards were in
  • the gluta ate- containing solution was then removed by aspiration and the cells were washed twice with Locke solution containing 1 mM Mg2S ⁇ 4, then returned to the incubator in their original medium. Cell survival was evaluated after 24 hours, according to the procedure by K.H. Johnes et al. J. Histochem, Cytochem. 33, 77 (1985).
  • Hippocampal slices were obtained from eight-day old Sprague-Dawley rats. Sections were prepared according to what described by J. Gathwaite et al., Neurosci. Lett. 97, 316 (1989). Transverse slices of hippocampus cut at a thickness of 0.5 mm by a Vibroslice (Campden Instruments LTD, U.K.), were submerged in 2 ml of a Krebs solution containing 11 mM glucose, equilibrated with 95% 0 2 - 5% C0 2 (pH 7.4), and preincubated at 37 °C for 30 min. After that, 30 ⁇ m NMDA was added and incubation was carried out for 30 min.
  • non-steroidal antiinflammatory compounds according to the invention have an unexpected capability of effectively counteracting neurodegenerative conditions, by acting directly at the level of neuronal cells. It should be noted, with respect to those compounds ' of the invention defined at point (a), that such a characteristic makes their pharmacological spectrum wider than that of other NSAIDs. Therefore, it is unexpectedly possible to use the compounds of the invention previously defined at point (a) also in patients affected with neurodegenerative diseases associated with glutamate-mediated neuronal damages but not with inflammatory conditions, since said compounds have such double and distinct capability of acting as both antiinflammatory and antidegenerative agents .

Abstract

La présente invention concerne l'utilisation de composés anti-inflammatoires non stéroïdiens pour la prévention et le traitement de maladies neurodégénératives, telles que la maladie d'Alzheimer ou la maladie de Parkinson.
PCT/EP1997/006323 1996-11-13 1997-11-13 Utilisation de composes anti-inflammatoires non steroidiens selectionnes pour la prevention et le traitement de maladies neurodegeneratives WO1998020864A2 (fr)

Applications Claiming Priority (2)

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IT96MI002356A ITMI962356A1 (it) 1996-11-13 1996-11-13 Uso di composti derivati da molecole ad attivita' antinfiammatoria di tipo non steroideo per la prevenzione e il trattamento di
ITMI96A002356 1996-11-13

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WO1998020864A9 true WO1998020864A9 (fr) 1998-08-27
WO1998020864A3 WO1998020864A3 (fr) 1998-10-15

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