Neurodegenerative diseases are a significant problem at a socio-economic and health level. Reference may be made to Parkinson's disease and Alzheimer's disease, which are the main causes of dementia in the population of Amer- ica and Europe, Creutzfeldt-Jacob syndrome caused by prion, and sleeping sickness caused by protozoa, including Trypanosoma brucei rhodensiense and Trypanosoma brucei gambiense. Sleeping sickness is one of the main causes of death in the African population.

The drugs currently available for the treatment of neurodegenerative diseases do not allow effective thera- pies and, therefore, the pharmacological treatment of these diseases is unsatisfactory.

Neurodegenerative disease are caused by the death of nerve cells, for example astrocytes, astroglia and neu- rons. These nerve cell degenerative processes are linked to the action of interferon-y (IFN-y) (Galimberti D. et al.

(1999) Biochem. Biophys. Res. Comm. 263,251-256; Hunot S. et al. (1999) J. Neurosci. 19 3440-3447; Blasko I. et al.

(1999) FAsEB J. 13 63-68; Suo Z. et al. (1998) Brain Res.

807 110-117; Delgado et al. (1998) J. Leukoc. Biol. 63 740- 745; Rossi F, Bianchini E. (1996) Biochem. Biophys. Res.

Co-un. 225 474-478; MedaL. et al (1995) Nature 374,647-

650) which, by activating a nuclear factor STAT1 (Signal transducers and activators of transcription 1), carries out the various pleiotropic actions (Boehm, U. et al. (1997) Annu. Rev. Immunol. 15,749-795; Kordula T. et al. (1998) J. Biol. Chem. 273 4112-4118; Kitamura Y. et al Neurosci. Lett. 237 17-20). Amongst the various actions of interferon-y in the cell, of particular importance is its ability to modulate the expression of an enzyme, inducible nitric oxide synthase (iNOS), which by producing large quantities of NO can kill off nerve cells. This explains why interferon-y is a cause of the onset of neurodegenera- tive diseases.

The need was felt for the availability of drugs for the prevention and treatment of neurodegenerative dis- eases, which would be particularly effective in inhibiting the activation of STAT1.

This technical problem was solved by using the com- pound epigallocatechin-3-gallate, or its derivatives.

As a result, the present invention also relates to the use of compounds with the following formula (I), or its derivatives in the prevention and treatment of neu- rodegenerative diseases:

(I) The activity of compounds with the formula (I) in neurodegenerative diseases was demonstrated in the present invention by means of an experimental in vitro model, us- ing U251 human glioblastoma cells. In this experiment it was demonstrated that, for example using epigallocatechin- 3-gallate (EGCG) as the invention compound, in a concen- tration of 5 M, the invention compounds are effective in the treatment of neurodegenerative diseases, inhibiting 50% of the maximal activation of STAT1 induced by inter- feron-y.

The compounds according to the present invention are normally used in the in vitro experiments (see the exam- ples) in doses of between 1 and 50 FM, preferably from 5 to 20 uM, in a DME culture, complete with 10% v/v of fetal bovine serum.

The Applicant found that STAT1 inhibition normally occurs in a dose-dependent manner.

The inhibitory action of the compounds according to the present invention in the neurodegenerative processes described above is not attributable to the anti-oxidant, anti-inflammatory or anti-tumor activity of the compounds with formula (I). Effectively, using U251 human glioblas- toma cells it was demonstrated that anti-oxidant, anti- inflammatory or anti-tumor drugs cannot inhibit activation of STAT1 induced by interferon-y (see the examples). Vita- min C was used as the anti-oxidant. This compound was not active even at a dose of 100 FM. The anti-inflammatory compound used was hydrocortisone, a steroidal anti- inflammatory drug. This compound was also inactive, even

at a dose of 100 AM. The non-steroidal anti-inflammatory drug Ibuprofen was used, and was not active at a dose of 400 AM. The anti-tumor compound used was cisplatin, which was not active at a dose of 17 M.

The Applicant demonstrated that in order to inhibit STAT1 activity, the structure of the compounds with for- mula (I) is specific: neither gallic acid nor epigallo- catechin, which are the two polyphenolic components of EGCG, have a STAT1 inhibitory action.

Epigallocatechin-3-gallate is available on the mar- ket. It is the main ingredient of green tea extract. The methods for its isolation are indicated in Merck Index Edition 12 in the above-mentioned literature.

Pharmaceutical formulations containing the compounds according to the present invention contain the usual vehi- cles and excipients. They may be in the form of tablets, capsules or in formulations suitable for parenteral ad- ministration.

Effective doses of the compounds according to the present invention are those typically used in clinical medicine for epigallocatechin-3-gallate, or lower.

Pharmaceutical formulations containing the compounds according to the present invention can be prepared using techniques well known to experts in the field. See, for example,"Remington's Pharmaceutical Sciences 15th Ed." Activation of the STAT1 system also plays an impor- tant part in other diseases, such as asthma (Guo F. H. et al. J. Immunol. 2000,164 (11) 6970-80; Sampath e al., J.

Clin. Invest. 1999,103 (9) 1353-61), diabetes (Hill N. J. et al., Diabetes 2000 49 (10) 1744-7; Sekine N. et al. J.

Cell Physiol. 2000 184 (1) 46-57), cardiovascular diseases (J. Biol. Chem. 2000 275 10002-8), obesity (Scarpace P. J et al., Neuropharmacology 2000,39 (10) 1872-9; Velloso L. A. et al. Cardiovasc. Res. 1998 272 (26) 16216-23). The products according to the present invention can also be used to treat these diseases.

The following examples illustrate the present inven- tion without limiting the scope of application.

EXAMPLE 1 The cell line of U251 human glioblastoma was culti- vated, at 37°C, in a DMEM 12-614 (Dulbecco's modified eagle medium BioWhittaker Co.) culture complete with 10% of fe- tal bovine serum. The serum was eliminated 4 hours before treatment with interferon-y (250 U/ml). The epigallocate- chin gallate concentration (R = H, indicated as EGCG) used was 1 AM ín the DMEM culture.

STAT1 activation was measured by means of EMSA (elec- trophoretic mobility shift assay). 10 tg of nuclear ex- tract (Osborn, L., Kunkel, S., and Nabel, G. J. (1989) Proc. Natl. Acad. Sci. USA 86,2336-2340) were incubated at room temperature for 20 minutes with [32p]-double- stranded oligonucleotide (5'-gtegaCATTTCCCCGTAAATCg-3') (Wagner, B. J., Hayes, T. E. f Hoban, C. J., and Cochran, B. H.

(1990) EMBO J. 9,4477-4484). The products were fraction- ated by means of electrophoresis on non-denaturing poly- acrylamide gel. The intensity of the delayed bands was measured using the Phosphorimager system (Molecular Dynam- ics, Sunnyvale, CA, USA).

The results are indicated in example 27.

EXAMPLE 2 Example 1 was repeated, but with a concentration of

2 FM in the DMEM culture.

The results are indicated in example 27.

EXAMPLE 3 Example 1 was repeated, but with a concentration of 5 FM in the DMEM culture.

The results are indicated in example 27.

EXAMPLE 4 Example 1 was repeated, but with a concentration of 10 FM in the DMEM culture.

The results are indicated in example 27.

EXAMPLE 5 Example 1 was repeated, but with a concentration of 20 FM in the DMEM culture.

The results are indicated in example 27.

EXAMPLE 6 Example 1 was repeated, but with a concentration of 50 FM in the DMEM culture.

The results are indicated in example 27.

EXAMPLES 7-10 comparison with an anti-oxidant compound In these examples vitamin C was used as an anti- oxidant compound for comparison, in concentrations of 10 jM, 20 M, 50 M and 100 uM in the DME culture.

The results are indicated in example 27.

EXAMPLES 11-14 Comparison with a steroidal anti-inflammatory com- pound In these examples hydrocortisone was used as a ster- oidal anti-inflammatory compound for comparison, in con- centrations of 10 p. 20 plM, 50 ju. M and 100 FM in the DMEM culture.

The results are indicated in example 27.

EXAMPLES 15-19 Comparison with a non-steroidal anti-inflammatory compound In these examples ibuprofen was used as a non- steroidal anti-inflammatory compound for comparison, in concentrations of 10 ßM, 50 FM, 100 FM, 200 uM and 400 p, M in the DMEM culture.

The results are indicated in example 27.

EXAMPLES 20-23 Comparison with an anti-tumor compound In these examples cisplatin was used as an anti-tumor compound for comparison, in ßM concentrations in the DMEM culture.

The results are indicated in example 27.

EXAMPLE 24 Comparison Examples 1 to 6 were repeated, but using epigallo- catechin as the active compound in place of EGCG. Epigal- catechin is one of the two polyphenolic components of EGCG. The results are indicated in example 27.

EXAMPLE 25 Comparison Examples 1 to 6 were repeated, but using gallic acid as the active compound in place of EGCG. Gallic acid is the second polyphenolic compound of EGCG. The results are indicated in example 27.

EXAMPLE 26 Comparison Example 1 was repeated, but using Interleukin 6 (IL- 6) instead of IFN-1 as the STAT1 activator. Interleukin 6 is a known STAT3 activator. HeLa human cell lines (human cervical tumor cells) were also used; or HepG2 human liver tumor cell lines; or MCF7 human breast tumor cell lines.

The compound to be tested was EGCG (50 uM), the com-

pound with formula (I) according to the present invention.

EXAMPLE 27 Results IFN-y rapidly induces strong STAT1 activation in the U251 human glioblastoma cell line.

All of the compounds according to the present inven- tion and those used for comparisons are added to the U251 cell culture half an hour before treatment with IFN-Y.