METHODS AND PHARMACEUTICAL COMPOSITIONS FOR DIFFERENTIALLY ALTERING GENE EXPRESSION TO PROVIDE NEUROPROTECTION FOR THE ANIMAL CENTRAL NERVOUS SYSTEM AGAINST THE EFFECTS OF ISCHEMIA, NEURODEGENERATION, TRAUMA AND METAL POISONING

摘要

Methods and pharmaceutical compositions for preconditioning and/or providing neuroprotection to the animal central nervous system against the effects of neurological disorders involving ischemia, trauma, metal poisoning and neurodegeneration, including the associated cognitive, behavioral and physical impairments. In one embodiment, the method is accomplished by stimulating and/or stabilizing hypoxia-inducible factor-1a (HIF-1a). HIF-1a is known to provide a neuroprotective benefit under ischemic conditions. In another embodiment, the method is accomplished by differentially reducing, inhibiting or preventing the increased expression of selected genes caused by neurological disorders. Patients at risk for certain diseases or disorders that are associated with risk for cerebral ischemia may benefit, e.g., those at risk for Alzheimer's disease, Parkinson's disease, Wilson's disease, Huntington's disease, thalassemia or stroke, or those patients having head or spinal cord injury. Patients undergoing certain medical procedures that may result in ischemia may also benefit. Initially, the possibility of ischemia or neurodegeneration is recognized. Intranasal therapeutic agents are administered to the upper third of the nasal cavity to bypass the blood-brain barrier and access the central nervous system directly to avoid unwanted and potentially lethal side effects. Therapeutic agents include those substances that interact with iron and/or copper such as iron chelators, copper chelators, and antioxidants. Particular examples of such therapeutic agents are the iron chelators deferoxamine (DFO) and deferasirox. Intranasal administration of DFO is known to stimulate and/or stabilize HIF-1a and provides an efficient and safe method for pre-conditioning the brain to protect against cerebral ischemia.