Panacea Pharmaceuticals, Inc. Presents New Findings on PAN-811 at 9th International Conference on Alzheimerís Disease and Related Disorders

GAITHERSBURG, Md., July 20 /PRNewswire/ -- Panacea Pharmaceuticals, Inc. announced today the presentaion of new findings on its lead compound, PAN-811, for stroke and other neurodegenerative diseases at the 9 th International Conference on Alzheimer's Disease & Related Disorders. The conference is the largest gathering of Alzheimer researchers in history and is being held from July 17 through 22 at the Pennsylvania Convention Center in Philadelphia, Pennsylvania.

The Company has developed and utilized several cell-based screening assays to identify candidates that are neuroprotective in acute neuronal damage conditions (e.g., stroke) as well as chronic neurodegenerative conditions (e.g., Alzheimerís disease). Recently, we identified PAN-811, a bioavailable small molecule that displays potent neuroprotection in our screening assays using multiple insults such as hypoxia, ischemia, peroxide treatments, neurotoxins, apoptosis inducers, and sodium channel opener. The mechanism of action of PAN-811 is multi-faceted, acting as an iron chelator, a free-radical scavenger, and a reactive oxygen species neutralizer. PAN-811 has shown a much wider spectrum of action and more potent protection than other known neuroprotectants.

Panacea also recently announced that it had entered into a Collaborative Research and Development Agreement (CRADA) with the Walter Reed Army Institute of Research (WRAIR), Division of Neurosciences, Department of Neuropharmacology and Molecular Biology, to evaluate the efficacy, toxicity, and mechanism of action of PAN-811 and its derivatives as neuroprotectants for global and focal ischemia. The scope of work includes examination of these compounds in an animal model of transient focal brain ischemia to evaluate in vivo efficacy and toxicity as a part of pre-clinical studies.

The three abstracts are presented here in their entirity.

A NEUROPROTECTANT, PAN-811, REPRESENTING A NOVEL NEUROPROTECTIVE APPROACH TO TREAT NEURODEGENERATIVE DISEASES

Zhi-Gang Jiang, Bijan Almassian, Valery Nelson, Hossein A. Ghanbari

Background: Hypoxia contributes to neuropathogenesis for both familial and sporadic Alzheimerís Diseases (AD). Age-related ischemia-like conditions promotes cellular calcium [Ca2+]i accumulation in the neurons carrying mutations of the presenilin-1 gene, leading a neuronal cell death. A transient hypoxia to normal cortical neurons could cause several abnormalities that occur in AD, including mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), phospho-tau, and amyloid beta protein precursor (APP) cleavage. Several lines of evidences indicate that [Ca2+]i and intracellular ROS increases play a major role in the onset and progression of neuropathgenesis of the AD. PAN-811 as a divalent metal chelator is in phase II clinical trials for cancer therapy, but we are exploring its neuroprotective properties. Objective(s): Our goals were to study PAN-811 neuroprotective properties. Methods: Cultured embryonic rat cortical neurons and human olfactory neuroepithelial (ON) cell model were assaulted in 18-hour hypoxia and 6-hour ischemia conditions respectively. MTS, LDH, Fura-Red, and DHR123 assays were employed 24 or 48 hours post insults to determine mitochondrial function, cell membrane leasing, [Ca2+]i and ROS levels respectively. The cells received different concentrations of PAN-811 for a duration from 24 hours prior to the insults to end of hypoxic experiment or to ischemic termination. Results: PAN-811 completely protects hypoxia-induced neuronal cell death, with an efficacy dose of 2uM and toxicity dose of 50uM. Moreover PAN-811 greatly decreases [Ca2+]i and ROS accumulations in hypoxia-treated neurons. We further examined the effect of PAN-811 on ROS accumulation in human ON cell model. Hypoglycemia or ischemia results in ROS over-production in the ON cells derived from both normal human donor and AD patient, causing shrinkage of the cell bodies that contains high level of ROS. PAN-811 significantly reduces in intracellular ROS level in the human ON cells and maintains their morphology. Our additional studies also indicated that PAN-811 efficiently blocks ischemia-induced neurotoxicity in vitro and in vivo. Conclusions: Our results indicate that PAN-811 represents a novel class of compounds, which is a potent neuroprotective candidate for both acute and chronic neurodegenerative diseases, including AD. This class of neuroprotectant agents offers a novel therapeutic strategy for treatment of Alzheimerís disease.

A POTENT NEUROPROTECTANT PAN-811 TARGETS OXIDATIVE STRESS IN OLFACTORY NEUROBLASTS (ONs) DERIVED FROM ALZHEIMERíS DISEASE PATIENTS

Weiying Pan, Chantee Dancik, Valery Nelson, Bijan Almassian, Hossein A. Ghanbari

Background: Alzheimerís disease (AD) is an age-dependent neurodegenerative disease that caused by failure of neuronal function. Recent evidence has demonstrated that increased oxidative stress is a prominent and early feature of vulnerable neurons in AD. Anti-oxidative stress therapy represents a promising approach to prevent or slow the progression of AD. A major limitation in the discovery of new and effective anti-oxidative stress drugs for AD is that the vulnerable neurons of the brain in AD patients can not be studied in a manipulatable system. Olfactory neurons (ONs) are the only neurons of the mammalian CNS that are able to regenerate throughout adult life. Olfactory neuroblasts (ONs), which can replicate in cell culture, exhibit many of in situ characteristics of olfactory neurons, such as the expression of neuron-specific enolase, olfactory marker protein, neurofilaments, and growth-associated protein 43. Moreover, the ONs derived from AD patients exhibit abnormal amyloid precursor protein (APP) processing and increased oxidative damage similar to those found in AD brain. Therefore, cultured ONs are a promising in vitro cellular model for identifying potent drug candidates against oxidative stress in AD. Objective(s): Here we employed this ON model to evaluate PAN-811, a potent neuroprotectant discovered in our laboratory, for AD therapy. Methods: Cultured ONs derived from AD-affected individuals and aged-matched normal controls were pre-treated with varying concentrations of PAN-811 or a vehicle, and then subjected to H2O2-induced oxidative stress. The cellular expression levels of the oxidative stress markers were evaluated by Immunocytochemical analysis. The ability of PAN-811 to reduce reactive oxygen species (ROS) generation in ONs derived from AD patients was assessed by DCF assay. Results: PAN-811 is capable of reducing oxidative stress in ONs derived from AD patients as well as age-matched normal controls and enhancing the ability of ONs derived from AD patients against H2O2-induced oxidative stress with an efficacy does of 10 uM. Moreover, PAN-811 attenuates ROS generation in ONs derived from AD patients in a does-dependent manner. Conclusions: These data suggest that PAN-811 represents a new and potential drug candidate to target oxidative stress for use in AD therapy.

A NOVEL NEUROPROTECTANT PAN-811 ATTENUATES OXIDATIVE STRESS INDUCED BY BOTH REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN NEURONAL CELLS

Weiying Pan, Chantee Dancik, Valery Nelson, Bijan Almassian, Hossein A. Ghanbari

Background: Oxidative stress plays a significant role in neuronal cell death associated with a variety of neurodegenerative diseases including Alzheimerís disease, Parksinsonís disease, Huntingtonís disease, and amyotrophic lateral sclerosis, as well as for pathological conditions such as ischemia/reperfusion and excitotoxicity. Oxidative stress is accountable for redox regulation involving reactive oxygen species (ROS) and reactive nitrogen species (RNS). Substances that can reduce oxidative stress are expected to be potential drug candidates in the therapy of these neurodegenerative diseases and related pathological conditions. Studies in our laboratory have identified several potent, neuroprotectants, PAN-811, LA-01 and LA-02, which are capable of reducing ROS generation in neuronal cells and protecting neuronal cells against H2O2 induced oxidative damage. Objective(s): Here we are reporting the efficacy of PAN-811, LA-01 and LA-02 against nitrosative stress caused by excessive RNS in neuronal cells. Methods: Cultured cortical neurons were pre-treated with PAN-811, LA-01, or LA-02 at final concentration of 0.1 uM, 1 uM, 10 uM and 20 uM or a vehicle for 24 hours, and then subjected to nitrosative stress induced by 3-Morpholinosydnonimine (SIN-1), a potent ONOO-generator. After 24 hours, the cultures were evaluated for viability and mitochondrial function using a standardized MTS Assay. The effect of PAN-811 on the expression levels of nitric oxide synthases (NOS), the synthetic enzymes for NO production, was evaluated by Western Blot. Results: Exposure of rat primary cortical neuronal cells to SIN-1 resulted in a decrease in cell viability, an increase in lipid peroxidation and the synthesis of 8-hydroxy-2-deoxyguanosine. PAN-811 was capable of protecting and rescuing neuronal cells from SIN-1 induced damage. In contrast, LA-01 and LA-02 failed to show significant neuroprotective effects against such damage. Conclusions: These studies indicate that the neuroprotective ability of PAN-811 is attributable not only to its capacity against ROS induced oxidative damage but also via its ability to protect neuronal cells against RNS induced nitrosative stress.

About Panacea Pharmaceuticals, Inc.

Panacea Pharmaceuticals, Inc. is an emerging biopharmaceutical company focused on utilizing functional genomics and proteomics to develop therapeutics and diagnostics for diseases with substantial unmet clinical need. The Company's product development focus is on novel proteins and biochemical pathways related to cellular regulation and cell cycle abnormalities in oncology as well as both acute and chronic neurodegenerative conditions such as hypoxia-induced cognitive impairment, Parkinson's disease, and Alzheimer's disease.

More information is available at http://www.PanaceaPharma.com.

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