CHARACTERIZATION OF THE SECONDARY DAMAGE AND EVALUATION OF NEW ANTIINFLAMMATORY TREATMENTS IN AN ANIMAL MODEL OF INTRACEREBRAL HEMORRHAGE BY MRI

INTRACEREBRAL HEMORRHAGE (ICH) IS A MAJOR CAUSE OF MORTALITY AND DISABILITY. THE INITIAL HEMATOMA TRIGGERS A CASCADE OF SECONDARY DAMAGE PROCESSES SUCH AS INFLAMMATION, RUPTURE OF THE BLOOD-BRAIN BARRIER, IRON TOXICITY AND OXIDATIVE STRESS. THESE CONSTITUTE POTENTIAL THERAPEUTIC TARGETS FOR INTERVENTION. MAGNETIC RESONANCE IMAGING (MRI) IS A COMMONLY USED TOOL IN THE CLINICAL MANAGEMENT OF ICH. HOWEVER, CAUSE AND SIGNIFICANT OF SOME OF IMAGE ALTERATIONS IS STILL NOT FULLY CLARIFIED. IN THIS SENSE, THE USE OF MRI IN ANIMAL MODELS OF ICH WILL ENABLE TO CHARACTERIZE THE TEMPORAL COURSE OF THE ALTERATIONS, ITS HISTOPATHOLOGICAL SUBSTRATE AND TO CORRELATE IT WITH THE EXPRESSION OF THERAPEUTIC TARGETS AND PERIPHERAL MARKERS OF INFLAMMATION AND TISSUE DAMAGE. THE MRI SEQUENCES TYPICALLY USED IN THE STUDY OF PATIENTS WITH ICH ARE T1, T2, FLAIR, DWI AND T2*. HOWEVER, THERE ARE OTHER SEQUENCES SUCH AS PROTON SPECTROSCOPY (1H-MRS), MAGNETIZATION TRANSFER (MTI) AND KURTOSIS (DKI) WHOSE USEFULNESS IN ICH IS LITTLE EXPLORED. THIS PROJECT AIMS TO INVESTIGATE THE POTENTIAL OF THESE SEQUENCES TO CHARACTERIZE SECONDARY DAMAGE IN ICH, ESTABLISH THE HISTOPATHOLOGICAL SUBSTRATE OF THE ALTERATIONS, AND CORRELATE THESE WITH PERIPHERAL MARKERS OF DAMAGE AND INFLAMMATION. NEW ANTI-INFLAMMATORY DRUGS HAVE BEEN APPROVED IN RECENT YEARS. SOME OF THEM, SUCH AS LEUKOTRIENE ANTAGONISTS, JAK1/2 INHIBITORS, PHOSPHODIESTERASE 4, IL1, IL6, IL17, IL2, IL23, TNFA, AND INFY COULD MODIFY SECONDARY DAMAGE IN ICH. INVESTIGATING THE USEFULNESS OF DRUGS APPROVED FOR OTHER INDICATIONS IN THE ICH SIMPLIFY THE DEVELOPMENT OF TREATMENTS FOR THIS DISEASE. THIS APPROACH AVOIDS THE HIGH COSTS OF THE DEVELOPMENT OF A NEW DRUG. SINCE THESE PRODUCTS ARE ALREADY APPROVED, THEY MAY BE EVALUATED DIRECTLY IN INDEPENDENT CLINICAL TRIALS IF THEY DEMONSTRATE EFFICACY IN ICH MODELS. THIS PROJECT WILL PROVIDE RELEVANT INFORMATION ON SECONDARY DAMAGE IN ICH AND CHARACTERIZE ITS MANIFESTATION IN CONVENTIONAL AND ADVANCED MRI SEQUENCES, AS WELL AS ITS TEMPORAL EVOLUTION. LIKEWISE, IT WILL ESTABLISH THE CORRELATION OF MRI ALTERATIONS WITH ITS TISSUE SUBSTRATE BY DETERMINING DAMAGE MARKERS, GLIAL ACTIVATION, EXPRESSION OF INFLAMMATORY MOLECULES, IRON ACCUMULATION AND OXIDATIVE STRESS. FINALLY, WE PROPOSE CARRYING OUT A REPOSITIONING STRATEGY TO IDENTIFY POSSIBLE CANDIDATES FOR THE TREATMENT OF ICH AMONG THE FOLLOWING ANTI-INFLAMMATORY OR IMMUNOMODULATORY DRUGS APPROVED FOR OTHER INDICATIONS. MONTELUKAST (LEUKOTRIENE ANTAGONIST), TOFACITINIB AND RUXOLITINIB (JAK INHIBITOR), ZILEUTON (LIPOXYGENASE INHIBITOR), ROFLUMILAST (PHOSPHODIESTERASE 4 INHIBITOR), ANAKINRA (IL1 ANTAGONIST), TOCILIZUMAB (IL6 INHIBITOR), SECUKINUMAB (IL-17 INHIBITOR), ECULIZUMAB (C5 PROTEIN INHIBITOR) AND ETANERCEPT (TNF-α INHIBITOR). IF A POSITIVE EFFECT OF ANY OF THESE DRUGS IS OBSERVED, EFFICACY CRITERIA WILL BE ESTABLISHED BASED ON MRI AND PERIPHERAL MARKERS THAT CAN SERVE AS ENDPOINTS IN SUBSEQUENT CLINICAL TRIALS.