Exploring Neuroprotective Drug Therapies for Intracerebral Hemorrhage

Abstract

Abstract. Intracerebral hemorrhage (ICH) is a devastating neurological disorder with high mortality and poor prognosis, for which virtually no effective drug therapies are available at present. Experimental animal models, based on intrastriatal injection of collagenase or autologous blood, have enabled great advances in elucidation of cellular/molecular events contributing to brain pathogenesis associated with ICH. Many lines of evidence indicate that blood constituents, including hemoglobin-derived products as well as proteases such as thrombin, play important roles in the pathogenic events. Inflammatory reactions involving neutrophils, activated microglia, and production of proinflammatory cytokines also constitute a critical aspect of pathology leading to neurodegeneration and tissue damage. Efforts are continuing to find drugs that potentially alleviate pathologi cal and neurological outcomes of ICH. Various drugs that possess antioxidative, antiinflammatory or neurotrophic/neuroprotective properties have been demonstrated to produce therapeutic effects on ICH animal models. Drugs already in clinical use such as minocycline, statins, and several nuclear receptor ligands are among the list of effective drugs, but whether they also show therapeutic efficacy in human ICH patients remains unproven. Here, current knowledge of ICH pathogenesis and problems arising with respect to exploration of new drug candidates are discussed.

Minocycline but not valproic acid influence the density of NogoA-immunoreactive neurons in the hilus of the dentate gyrus of the rats subjected to intracerebral haematoma

“…Valproic acid and minocycline has been considered a neuroprotective agents in several models of brain injuries and diseases [18,23,35,43]. Neuroprotective effect of minocycline may be attributable to its antiapoptotic, antioxidative and anti-inflammatory actions [18,22].…”

“…Neuroprotective effect of minocycline may be attributable to its antiapoptotic, antioxidative and anti-inflammatory actions [18,22]. In the experimental models of intracerebral haemorrhage models minocycline was shown to inhibit some inflammatory-related genes [42] as well as microglial/macrophage activation in peri-infarct region [43].…”

Blood Glutamate Grabbing Does Not Reduce the Hematoma in an Intracerebral Hemorrhage Model but it is a Safe Excitotoxic Treatment Modality

“…Primary damage is followed by a secondary damage mainly characterized by edema formation, tissular ischemia, and glutamate excitotoxicity. 2 Depending on the underlying cause of bleeding, ICH originates from the spontaneous rupture of small arteries or arterioles damaged because of two major factors: hypertensive arteriolosclerosis and amyloid angiopathy, which accounts for 78% to 88% of cases. Other cases of ICH occur in a minority of patients in association with coagulopathy, brain tumors, aneurysms, vascular anomalies, and thrombolytic treatment of ischemic stroke (reviewed in Wang and Dore 1 ).…”

Emerging experimental therapies for intracerebral hemorrhage: targeting mechanisms of secondary brain injury

“…4 Extravasation of blood products into brain parenchyma initiates hematoma formation, edema, and cell death. 34 Hematoma development and resultant mass effect account for the initial neurological deficits associated with ICH.…”

“…31, 34 Wasserman and colleagues 83,85 used a rat ICH model to demonstrate that daily systemic administration of minocycline, starting 6 hours after collagenase injection, reduced TNF-a and MMP-12 expression. Minocycline also preserved BBB integrity, attenuated edema formation, and limited neutrophil infiltration.…”