The overall goal of this proposal is to examine the ability of two novel drugs to prevent brain damage and memory loss in an animal model of Alzheimer's Disease (AD). These drugs, called SanFlow and VACNO, were invented and developed by our collaborator Dr. Hsia at AntiRadical Therapeutics. Both drugs act as extracellular superoxide dismutase (SOD) mimetics and have been shown to be neuroprotective in models of stroke and traumatic brain injury. We have also recently shown that VACNO prevents damage to the hippocampus by cancer chemotherapy drugs. Damage to this area of the brain is associated with ?chemobrain? in cancer patients and is thought to lead to cognitive and memory impairment in these patients. Therefore, we hypothesize that VACNO and/or SanFlow, will be effective therapeutics against progression of AD. This hypothesis is strengthened by the fact that AD is associated with oxidative stress leading to neuroinflammation and vascular dysfunction. VACNO and SanFlow have been shown to prevent or reverse all of these pathologies in brain tissue in other disease models. However, these drugs have never been tested in a model of AD and that is the goal of the studies proposed here. For this, we will use the scopolamine-induced model of AD. This model has been validated in rodents and in humans to cause changes similar to those of AD, including cognitive and memory deficits. Our studies will be performed in rats, which will be injected with scopolamine at doses that have been shown to cause AD-like symptoms, including memory and learning deficits.
In Aim 1 SanFlow will be tested for its ability to therapeutically prevent or reverse the effects on memory and learning. This will be performed using a Morris water maze test or a step-through inhibitory avoidance test, both of which have been used to measure memory in animal models of AD. We will also test SanFlow in combination with donepezil, a cholinesterase inhibitor that has FDA approval for treatment of AD but provides very limited benefit to patients. Since SanFlow has a completely different mechanism of action, it is conceivable that the combination will act synergistically to provide major therapeutic responses.
For Aim 2, the same experiments will be performed for VACNO. Although SanFlow and VACNO are both superoxide dismutase mimetic drugs, they also have significant differences. SanFlow, produced from hemoglobin, has both strong SOD and catalase mimetic activity but is limited to vascular distribution upon injection. VACNO, on the other hand, is a strong SOD mimetic that can distribute to both the vasculature and interstitial spaces. These differences may allow one of the drugs to provide better protection from cognitive dysfunction associated with AD. With the studies proposed here, we expect to determine if our macromolecular SOD mimetic drugs are able to reduce memory loss in an animal model of AD. If this is substantiated, we will undertake future studies to understand the mechanism of action and the associated effects on brain tissue. An advantage of the scopolamine-induced model is that the drug is approved for other uses in humans, and it has been used in human clinical trials to test potential AD therapeutics to prevent memory loss.
The goal of the proposed research is to examine the ability of two novel drugs to reverse or prevent memory loss in an animal model of Alzheimer's disease. The drugs are proprietary macromolecular antioxidants that are known to protect the brain from stroke damage and from chemotherapy damage. Since oxidative damage leading to vasculature defects is associated with Alzheimer's, it is predicted that our drugs will prevent or reverse memory loss associated with the progression of the disease.
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