- Email: [email protected]
P1-365 A neuroprotectant, PAN-811, representing a novel neuroprotective approach to treat neurodegenerative diseases
$202
Poster Session PI : Therapeutics and Therapeutic Strategies- Therapeutic Strategies, Behavioral Symptoms
(78%), daily living activities (86%). Families of G2 patients noted an improvement or stabilization of memory (61%), language (79%), mood (74%), behavior (67%), daily living activities (67%). Globally, 47% of the patients were improved or stabilized in all of the five domains. Conclusions: Discontinuations are most frequent when the treatment is a second intention one. Mild gastrointestinal troubles are the most frequent AE. After one year, improvement and stabilization observed by families are more significant than the results of MMSE. Thus, galantamine can contribute to lessen the caregivers' burden and to enhance a more acceptable stay at home.
~
A
NEUROPROTECTANT, PAN-811, REPRESENTING A NOVEL NEUROPROTECTIVE APPROACH TO
TREAT NEURODEGENERATIVE DISEASES Zhi-Gang Jiang*, Bijan Almassian, Valery Nelson, Hossein A. Ghanbari. Panacea Pharmaceuticals, Inc., Gaithersburg, MD, USA. Contact e-mail: zg]iang @panaceapharma, corn
Background: Hypoxia contributes to neuropathogenesis for both familial and sporadic Alzheimer's 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, includirig 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 2 IxM and toxicity dose of 50 t*M. Moreover PAN-811 greatly decreases [Ca2+]i and ROS accumulations in hypoxia-treated neurons. We further examined the effect o f 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 Alzheimer's disease.
•
PRECLINICAL EFFICACY OF MEM 1003 IN A TASK SENSISTIVE TO ALZHEIMER'S DISEASE
Diana S. Woodruff-Pak* 1,2, Gregory M. Rose 3. 1Temple University, Philadelphia, PA, USA; 2Albert Einstein Healthcare Network, Philadelphia, PA, USA; 3Memory Pharmaceuticals Corp., Montvale, NJ, USA. Contact e-mail: [email protected] Background: Eyeblink classical conditioning is a learning paradigm that shows neurobiologicai and behavioral parallels across several species of mammals, including humans. Because eyeblink conditioning effectively discriminates patients with Alzheimer's disease (AD) from healthy older adults, preclinical studies using this paradigm could have direct relevance for clinical trials. Objective: The aim of these experiments was to evaluate whether a novel L-type calcium channel blocker, MEM 1003, would improve eyeblink conditioning in aged rabbits. Two different paradigms were tested: delay and trace eyeblink classical conditioning. Methods: 109 retired breeder female specific pathogen free (SPF) New Zealand white rabbits, averaging 33.5 months old, were trained with 0 (vehicle), 1, 2, 3, or 10 mg/kg MEM 1003 in the 750 ms delay eyeblink conditioning procedure or with 0, 1, 2, or 3 mg/kg MEM 1003 in the 600 ms trace eyeblink conditioning procedure. All rabbits received subcutaneous injections of the drug 30 minutes prior to each training session. There were 15 daily sessions of 90 paired presentations of a tone (conditioned stimulus) and corneal airpuff (unconditioned stimulus). Two additional groups of rabbits received 0 or 3 mg/kg MEM 1003 in an explicitly unpaired control conditioning procedure. Results: MEM 1003 had no effect on rabbits tested in using the unpaired protocol. By contrast, MEM 1003 significantly improved learning in both the delay and trace conditioning procedures. Using trials to learning criterion, a measure for which a lower score indicates faster learning, U-shaped functions were observed in both paradigms. (See Figure.) For delay conditioning doses of 2 and 3 mg/kg were effective, while for the trace procedure the dose of 2 mg/kg, but not 3 mg/kg, enhanced learning compared to the vehicle-treated control group. Conclusions: MEM 1003 shows efficacy in delay and trace eyeblink classical conditioning in older rabbits. Because of eyeblink conditioning's sensitivity to AD, these results suggest that MEM 1003 could be of benefit to AD patients.
•
TOLERABILITY, SAFETY AND EFFICACY IN PATIENTS WITH ALZHEIMER'S DISEASE WHO ARE SWITCHED FROM DONEPEZIL TO GALANTAMINE
Alexander F. Kurz* 1, Michael Gold 2. 1Technische Universitaet Munchen, Munich, Germany; 2Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ, USA. Contact e-mail: alexander.kurz @lrz.tu-muenchen.de
Background: Galantamine is a reversible acetylcholinesterase inhibitor
ms Delay
(AChEI) as well as an allosteric modulator of nicotinic acetylcholine receptors. Currentl~ll0nl~l~z'i[r~(:~e most commonly prescribed AChEI (AD), however some causing the treating
e,
Abstract P1-366 - Fig. 1.
Poster Session PI : Therapeutics and Therapeutic Strategies- Therapeutic Strategies, Behavioral Symptoms
(78%), daily living activities (86%). Families of G2 patients noted an improvement or stabilization of memory (61%), language (79%), mood (74%), behavior (67%), daily living activities (67%). Globally, 47% of the patients were improved or stabilized in all of the five domains. Conclusions: Discontinuations are most frequent when the treatment is a second intention one. Mild gastrointestinal troubles are the most frequent AE. After one year, improvement and stabilization observed by families are more significant than the results of MMSE. Thus, galantamine can contribute to lessen the caregivers' burden and to enhance a more acceptable stay at home.
~
A
NEUROPROTECTANT, PAN-811, REPRESENTING A NOVEL NEUROPROTECTIVE APPROACH TO
TREAT NEURODEGENERATIVE DISEASES Zhi-Gang Jiang*, Bijan Almassian, Valery Nelson, Hossein A. Ghanbari. Panacea Pharmaceuticals, Inc., Gaithersburg, MD, USA. Contact e-mail: zg]iang @panaceapharma, corn
Background: Hypoxia contributes to neuropathogenesis for both familial and sporadic Alzheimer's 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, includirig 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 2 IxM and toxicity dose of 50 t*M. Moreover PAN-811 greatly decreases [Ca2+]i and ROS accumulations in hypoxia-treated neurons. We further examined the effect o f 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 Alzheimer's disease.
•
PRECLINICAL EFFICACY OF MEM 1003 IN A TASK SENSISTIVE TO ALZHEIMER'S DISEASE
Diana S. Woodruff-Pak* 1,2, Gregory M. Rose 3. 1Temple University, Philadelphia, PA, USA; 2Albert Einstein Healthcare Network, Philadelphia, PA, USA; 3Memory Pharmaceuticals Corp., Montvale, NJ, USA. Contact e-mail: [email protected] Background: Eyeblink classical conditioning is a learning paradigm that shows neurobiologicai and behavioral parallels across several species of mammals, including humans. Because eyeblink conditioning effectively discriminates patients with Alzheimer's disease (AD) from healthy older adults, preclinical studies using this paradigm could have direct relevance for clinical trials. Objective: The aim of these experiments was to evaluate whether a novel L-type calcium channel blocker, MEM 1003, would improve eyeblink conditioning in aged rabbits. Two different paradigms were tested: delay and trace eyeblink classical conditioning. Methods: 109 retired breeder female specific pathogen free (SPF) New Zealand white rabbits, averaging 33.5 months old, were trained with 0 (vehicle), 1, 2, 3, or 10 mg/kg MEM 1003 in the 750 ms delay eyeblink conditioning procedure or with 0, 1, 2, or 3 mg/kg MEM 1003 in the 600 ms trace eyeblink conditioning procedure. All rabbits received subcutaneous injections of the drug 30 minutes prior to each training session. There were 15 daily sessions of 90 paired presentations of a tone (conditioned stimulus) and corneal airpuff (unconditioned stimulus). Two additional groups of rabbits received 0 or 3 mg/kg MEM 1003 in an explicitly unpaired control conditioning procedure. Results: MEM 1003 had no effect on rabbits tested in using the unpaired protocol. By contrast, MEM 1003 significantly improved learning in both the delay and trace conditioning procedures. Using trials to learning criterion, a measure for which a lower score indicates faster learning, U-shaped functions were observed in both paradigms. (See Figure.) For delay conditioning doses of 2 and 3 mg/kg were effective, while for the trace procedure the dose of 2 mg/kg, but not 3 mg/kg, enhanced learning compared to the vehicle-treated control group. Conclusions: MEM 1003 shows efficacy in delay and trace eyeblink classical conditioning in older rabbits. Because of eyeblink conditioning's sensitivity to AD, these results suggest that MEM 1003 could be of benefit to AD patients.
•
TOLERABILITY, SAFETY AND EFFICACY IN PATIENTS WITH ALZHEIMER'S DISEASE WHO ARE SWITCHED FROM DONEPEZIL TO GALANTAMINE
Alexander F. Kurz* 1, Michael Gold 2. 1Technische Universitaet Munchen, Munich, Germany; 2Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ, USA. Contact e-mail: alexander.kurz @lrz.tu-muenchen.de
Background: Galantamine is a reversible acetylcholinesterase inhibitor
ms Delay
(AChEI) as well as an allosteric modulator of nicotinic acetylcholine receptors. Currentl~ll0nl~l~z'i[r~(:~e most commonly prescribed AChEI (AD), however some causing the treating
e,
Abstract P1-366 - Fig. 1.