Neural injury associated with traumatic brain injury, stroke/ischemia, hypoxic stress, and excitotoxicity represents a long-standing public health problem. For example, stroke is the third leading cause of death in the United States and the leading cause of adult disability. With the aging of the population, the number of stroke patients in the US is likely to grow. Current models describing acute neural injury or excitotoxic injury, such as during ischemia and reperfusion (I/R) injury, center on the concept of calcium (Ca2+) ion accumulation leading to cell death. However, experimental treatments targeting Ca2+ homeostasis have not been very successful in reducing the volume or severity of neuronal damage. Accumulating evidence suggests that another divalent ion zinc (Zn2+) is also involved in excitotoxic neuronal death after head trauma, epilepsy, cerebral ischemia and reperfusion. The long-term goal of this research approach is to develop new therapeutic modalities to prevent or attenuate brain injury in patients who have suffered stroke or heart attack. The objective of this proposal is to determine the action of Zn2+ and to determine the relationships of Zn2+ transient with Ca2+ transient in ischemia and reperfusion. Our preliminary data shows that oxygen glucose deprivation (OGD) induces an elevation of intracellular Zn2+ that plays a role in the regulation of functional consequences after the injury. The evidence of elevated Zn2+ has posed a dilemma since most fluorescent Ca2+ probes and Ca2+ chelators also bind with high affinity to Zn2+. We have shown that rising Zn2+ is the primary source of the Ca2+ transient conventionally measured with fluorescent """"""""calcium specific"""""""" indicators.
In Specific Aim 1 this proposal will test the hypothesis that Zn2+ elevation is the causal factor of neuronal damage under conditions of ODG. The elevation of Zn2+ triggers a cascade of events changing in the brain function.
In Specific Aim 2, we will determine the source of Zn2+ accumulation upon acute brain injury, and to study the Zn2+ release from thapsigargin sensitive Ca2+ storages. In preliminary studies thapsigargin induced an increase of Zn2+ transient stained with Zn2+ indicator. This observation with other data prompt us to hypothesize that the accumulated Zn2+ during neuronal injury is also being released from thapsigargin sensitive storage(s) implicated before for Ca2+ overloading, and that Ca2+ storages may also be the site of storage for Zn2+. The long-term goal of the project is to elucidate novel regulatory mechanisms for neuronal injury and to identify new therapeutic modalities or rehabilitation strategies to prevent or attenuate neurodegenerative disorders after acute brain injury.
Neurological disorders associated with traumatic brain injury, ischemic stroke, hypoxia, and excitotoxicity represents a long-standing public health problem. Thus, the ability to identify the cellular and molecular mechanism specific to the acute neural injury that may initiate neurodegeneration is of clinical importance. We will determine the role of Zn2+ or Zn2+ dyshomeostasis in neural injury. Therefore, the proposed studies address an important aspect of the mechanisms/pathophysiology of neurological disorders that need to be examined in greater detail.
