- Email: [email protected]
P1-342 Cholinergic regulation of microglial activation in response to abeta
Poster Session PI : Therapeutics and Therapeutic Strategies- Therapeutic Strategies, Behavioral Symptoms
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L O N G - T E R M T R E A T M E N T W I T H GALANTAMINE OF PATIENTS WITH ALZHEIMER'S DISEASE LEADS TO A BROAD SPECTRUM OF BENEFICIAL EFFECTS
Andreas Schmitt* l, Andreas Schreiner 1, Klaus Hager 2. 1janssen-Cilag, Neuss, Germany; 2Klinik fiir Rehabilitation and Geriatrie, Henriettenstiftung, Hannover, Germany. Contact e-mail: aschmit3 @jacde.jnj.com Baekground: Several clinical trials have demonstrated the efficacy and safety of galantamine in the treatment of patients with mild to moderate Alzheimer's Disease (AD). Galantamine's unique mode of action, the inhibition of the acetyl choline esterase and the enhancement of nicotinic neurotransmission, addresses systems known to be markedly impaired in AD patients. Objective(s): In this open-label study, the efficacy mad tolerability of 2-year treatment with galantamine in AD patients were investigated. Methods: Patients with mild to moderate AD (NINCDS-ADRDA criteria) were included into a 2-year, multicenter, open-label study conducted in Germany. The Alzheimer's Disease Assessment Scale (ADAS-cog) was used as primary efficacy parameter for measuring cognitive function. The secondary efficacy parameters were the Bayer-ADL-score (B-ADL) for evaluating the activities of daily living (ADL) and the Neuropsychiatric Inventory (NPI) for analyzing the behavioural and psychological symptoms of dementia (BPSD). Physicians rated the clinical global impression of treatment effect with the CGI-scale. Statistical analyses were based on the ITT population. Results: 86 patients (mean age: 71y; f: m = 64% : 36%, mean ADAS-cog 22.4) were treated with a dally dose of 24 mg or 16 mg, respectively. After initial significant improvement on the ADAS-cog-scale at 3 and 6 months, a slow decline was observed, crossing baseline between 12 and 18 months and reaching 2.5 points below baseline after 2 years. The NPI-score revealed a significant improvement of BPSD between 3-12 months, followed by a slow decline reaching baseline levels after 2 years. The Bayer-ADL-score showed a slow decline in ADL over the whole study period. In line with these results, the CGI-evaluation showed improvement or stabilization in 55% of the patients. The treatment with galantamine was well tolerated. Adverse events included nausea (6.4%), dizziness (4.6%) and headache (2.7%). Conclusions: This 2-year study demonstrates that the treatment with galantamine leads to significant improvement of cognition mad BPSD during the first year, and resulting in substantial slowing of the progression of AD symptoms over the whole study period. These results may reflect the clinical relevance of galantamine's dual mode of action including enhanced nicotinic neurotransmission.
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CHOLINERGIC REGULATION OF MICROGLIAL ACTIVATION IN RESPONSE TO ABETA
R. Douglas Shytle* 1, Kirk Townsend 2, Jared Ehrhart 2, Nan Sun 2, Jin Zeng 2, Paul R. Sanberg 1, Jun Tan 2. 1Center for Excellence in Aging
and Brain Repair, Dept. of Neurosurgery, Tampa, FL, USA; 2Neuroimmunlogy Division, Institute for Research in Psychiatry, University of South Florida, Tampa, FL, USA. Contact e-mail: [email protected] Background: Alzheimer amyloid plaque formation involves processes such as 13-amyloid (AI3) deposition that can activate microglia-mediated inflammatory responses. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not well known. Objective: In the peripheral nervous system, an endogenous "cholinergic anti-inflammatory pathway" regulates systemic inflammatory responses via the principle vagal neurotransmitter, acetylcholine (ACh), acting at c~7 nicotinic acetylcholinergic receptors (nAChR) found on blood born macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. We have recently reported that cultured microglial cells express c~7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent and immunochistochemistry analyses. Moreover, ACh and nicotine pretreatment inhibited LPS-induced TNF-c~ release in marine derived microglial cells through a reduction in phosphorylation of p44/42
S195
and p38 MAPK pathways, an effect attenuated by ~7 selective nicotinic antagonist, c~-bungarotoxin. Our current objective was to determine if cholinergie signaling regulates microglial activation mediated by A[3. Methods and Results: We report for the first time that ACh, nicotine, and choline inhibit Al3-induced innate immune responses in routine microglial cells as evidenced by decreased production of TNF-c~, IL-6, and IL-1[3 and increased microglial phagocytosis of exogenous A~3 peptides. Coneluslons: Our findings uncover a brain cholinergic pathway that regulates A[3 mediated microglial activation through ~7 nAChRs. We hypothesize that the loss of cholinergic communication in Alzheimer's disease may be partially responsible for the turning of microglia to a hyperactivated state, which allows them to escape neuronal control and to give rise to persistent inflammation. Acknowledgements: This work was supported by grants from the Florida Alzheimer Disease Center & Research Institute (RDS and JT) and Alzheimer Association (JT).
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MEMANTINE IS SAFE FOR SHORT- AND LONG-TERM TREATMENT OF DEMENTIA
Stephen M. Graham .1 , Jeffrey M. Jonas 1, Grace S. Lee 1, Margaret Ann Goetz 1, Albrecht Sttffler 2, Yvonne Wirth 2. 1Forest Research
Institute, Jersey City, NJ, USA; 2Merz Pharmaceuticals GmbH, Frankfurt~Main, Germany. Contact e-mail: [email protected] Background: Memantine, a low-moderate affinity, uncompetitive NMDA receptor antagonist, was approved in the U.S. for the treatment of moderate to severe Alzheimer's disease (AD) in October 2003. Short- and longterm safety and tolerability of memanfine for the treatment of dementia were assessed through five donhle-blind, placebo-controlled trials and five open-label extension studies. Objective(s): To evaluate the shortand long-term safety and tolerability of memantine for the treatment of dementia. Methods: The short-term safety of memantine in moderate to severe AD patients (n = 734; memantine 10-20 rag/day; 12-28 weeks) was assessed in three of the five double-blind, placebo-controlled trials. Two other double-blind trials examined 900 mild to moderate vascular dementia (VaD) patients administered 20 rag/day memantine or placebo for 28 weeks. Long-term safety of memantine was assessed by pooling data from five open-label extension studies with moderate to severe AD and VaD patients. Safety parameters included adverse events (AEs), vital signs and clinical laboratory tests. Results: In the evaluation of short-term safety, only headache and confusion were reported in >5% of moderate to severe memantine-treated AD patients at an incidence of at least twice that of placebo. Only constipation was reported in >_.5% of memantine-treated VaD patients at an incidence of at least twice that of placebo. The overall profile of AEs reported in the long-term, open-label studies was similar to that reported in the short-term, double-blind studies. The majority of AEs reported in all studies were considered mild or moderate in severity and not related to memantine. No clinically relevant differences between memanfine and placebo patients in the vital signs or laboratory values were observed. Conclusions: The short- and long-term treatment of dementia with memantine is safe and well tolerated.
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DONEPEZIL IS SAFE A N D W E L L T O L E R A T E D IN ALZHEIMER'S DISEASE PATIENTS, AT DOSES OF UP TO 20 MG/DAY
R. Schindler .1 , R. Zhang I , J.R. Ieni 2, H. Li 2. lPfizer, New York, NY, USA;
2Eisai lnc, Teaneck, NJ, USA. Contact e-mail: [email protected] Background: The acetylcholinesterase inhibitor, donepezil, is approved for the treatment of mild to moderate Alzheimer's disease (AD) at doses up to 10 rag/day and is well tolerated; it is possible that a higher dose, if tolerated, might provide greater benefits. Objective: To determine the safety and tolerability of treatment with 15 or 20 rag/day donepezil in mild to moderate AD. Methods: This was a 2-center, randomized, double-blind, placebo-controlled study of higher dose donepezil (15 or 20 rag/day). Patients with mild to moderate AD (MMSE 10-26) currently receiving 10 mg/day donepezil were randomized to receive either higher dose donepezil
•
L O N G - T E R M T R E A T M E N T W I T H GALANTAMINE OF PATIENTS WITH ALZHEIMER'S DISEASE LEADS TO A BROAD SPECTRUM OF BENEFICIAL EFFECTS
Andreas Schmitt* l, Andreas Schreiner 1, Klaus Hager 2. 1janssen-Cilag, Neuss, Germany; 2Klinik fiir Rehabilitation and Geriatrie, Henriettenstiftung, Hannover, Germany. Contact e-mail: aschmit3 @jacde.jnj.com Baekground: Several clinical trials have demonstrated the efficacy and safety of galantamine in the treatment of patients with mild to moderate Alzheimer's Disease (AD). Galantamine's unique mode of action, the inhibition of the acetyl choline esterase and the enhancement of nicotinic neurotransmission, addresses systems known to be markedly impaired in AD patients. Objective(s): In this open-label study, the efficacy mad tolerability of 2-year treatment with galantamine in AD patients were investigated. Methods: Patients with mild to moderate AD (NINCDS-ADRDA criteria) were included into a 2-year, multicenter, open-label study conducted in Germany. The Alzheimer's Disease Assessment Scale (ADAS-cog) was used as primary efficacy parameter for measuring cognitive function. The secondary efficacy parameters were the Bayer-ADL-score (B-ADL) for evaluating the activities of daily living (ADL) and the Neuropsychiatric Inventory (NPI) for analyzing the behavioural and psychological symptoms of dementia (BPSD). Physicians rated the clinical global impression of treatment effect with the CGI-scale. Statistical analyses were based on the ITT population. Results: 86 patients (mean age: 71y; f: m = 64% : 36%, mean ADAS-cog 22.4) were treated with a dally dose of 24 mg or 16 mg, respectively. After initial significant improvement on the ADAS-cog-scale at 3 and 6 months, a slow decline was observed, crossing baseline between 12 and 18 months and reaching 2.5 points below baseline after 2 years. The NPI-score revealed a significant improvement of BPSD between 3-12 months, followed by a slow decline reaching baseline levels after 2 years. The Bayer-ADL-score showed a slow decline in ADL over the whole study period. In line with these results, the CGI-evaluation showed improvement or stabilization in 55% of the patients. The treatment with galantamine was well tolerated. Adverse events included nausea (6.4%), dizziness (4.6%) and headache (2.7%). Conclusions: This 2-year study demonstrates that the treatment with galantamine leads to significant improvement of cognition mad BPSD during the first year, and resulting in substantial slowing of the progression of AD symptoms over the whole study period. These results may reflect the clinical relevance of galantamine's dual mode of action including enhanced nicotinic neurotransmission.
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CHOLINERGIC REGULATION OF MICROGLIAL ACTIVATION IN RESPONSE TO ABETA
R. Douglas Shytle* 1, Kirk Townsend 2, Jared Ehrhart 2, Nan Sun 2, Jin Zeng 2, Paul R. Sanberg 1, Jun Tan 2. 1Center for Excellence in Aging
and Brain Repair, Dept. of Neurosurgery, Tampa, FL, USA; 2Neuroimmunlogy Division, Institute for Research in Psychiatry, University of South Florida, Tampa, FL, USA. Contact e-mail: [email protected] Background: Alzheimer amyloid plaque formation involves processes such as 13-amyloid (AI3) deposition that can activate microglia-mediated inflammatory responses. While it is recognized that healthy neurons and astrocytes regulate the magnitude of microglia-mediated innate immune responses and limit excessive CNS inflammation, the endogenous signals governing this process are not well known. Objective: In the peripheral nervous system, an endogenous "cholinergic anti-inflammatory pathway" regulates systemic inflammatory responses via the principle vagal neurotransmitter, acetylcholine (ACh), acting at c~7 nicotinic acetylcholinergic receptors (nAChR) found on blood born macrophages. These data led us to investigate whether a similar cholinergic pathway exists in the brain that could regulate microglial activation. We have recently reported that cultured microglial cells express c~7 nAChR subunit as determined by RT-PCR, western blot, immunofluorescent and immunochistochemistry analyses. Moreover, ACh and nicotine pretreatment inhibited LPS-induced TNF-c~ release in marine derived microglial cells through a reduction in phosphorylation of p44/42
S195
and p38 MAPK pathways, an effect attenuated by ~7 selective nicotinic antagonist, c~-bungarotoxin. Our current objective was to determine if cholinergie signaling regulates microglial activation mediated by A[3. Methods and Results: We report for the first time that ACh, nicotine, and choline inhibit Al3-induced innate immune responses in routine microglial cells as evidenced by decreased production of TNF-c~, IL-6, and IL-1[3 and increased microglial phagocytosis of exogenous A~3 peptides. Coneluslons: Our findings uncover a brain cholinergic pathway that regulates A[3 mediated microglial activation through ~7 nAChRs. We hypothesize that the loss of cholinergic communication in Alzheimer's disease may be partially responsible for the turning of microglia to a hyperactivated state, which allows them to escape neuronal control and to give rise to persistent inflammation. Acknowledgements: This work was supported by grants from the Florida Alzheimer Disease Center & Research Institute (RDS and JT) and Alzheimer Association (JT).
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MEMANTINE IS SAFE FOR SHORT- AND LONG-TERM TREATMENT OF DEMENTIA
Stephen M. Graham .1 , Jeffrey M. Jonas 1, Grace S. Lee 1, Margaret Ann Goetz 1, Albrecht Sttffler 2, Yvonne Wirth 2. 1Forest Research
Institute, Jersey City, NJ, USA; 2Merz Pharmaceuticals GmbH, Frankfurt~Main, Germany. Contact e-mail: [email protected] Background: Memantine, a low-moderate affinity, uncompetitive NMDA receptor antagonist, was approved in the U.S. for the treatment of moderate to severe Alzheimer's disease (AD) in October 2003. Short- and longterm safety and tolerability of memanfine for the treatment of dementia were assessed through five donhle-blind, placebo-controlled trials and five open-label extension studies. Objective(s): To evaluate the shortand long-term safety and tolerability of memantine for the treatment of dementia. Methods: The short-term safety of memantine in moderate to severe AD patients (n = 734; memantine 10-20 rag/day; 12-28 weeks) was assessed in three of the five double-blind, placebo-controlled trials. Two other double-blind trials examined 900 mild to moderate vascular dementia (VaD) patients administered 20 rag/day memantine or placebo for 28 weeks. Long-term safety of memantine was assessed by pooling data from five open-label extension studies with moderate to severe AD and VaD patients. Safety parameters included adverse events (AEs), vital signs and clinical laboratory tests. Results: In the evaluation of short-term safety, only headache and confusion were reported in >5% of moderate to severe memantine-treated AD patients at an incidence of at least twice that of placebo. Only constipation was reported in >_.5% of memantine-treated VaD patients at an incidence of at least twice that of placebo. The overall profile of AEs reported in the long-term, open-label studies was similar to that reported in the short-term, double-blind studies. The majority of AEs reported in all studies were considered mild or moderate in severity and not related to memantine. No clinically relevant differences between memanfine and placebo patients in the vital signs or laboratory values were observed. Conclusions: The short- and long-term treatment of dementia with memantine is safe and well tolerated.
•
DONEPEZIL IS SAFE A N D W E L L T O L E R A T E D IN ALZHEIMER'S DISEASE PATIENTS, AT DOSES OF UP TO 20 MG/DAY
R. Schindler .1 , R. Zhang I , J.R. Ieni 2, H. Li 2. lPfizer, New York, NY, USA;
2Eisai lnc, Teaneck, NJ, USA. Contact e-mail: [email protected] Background: The acetylcholinesterase inhibitor, donepezil, is approved for the treatment of mild to moderate Alzheimer's disease (AD) at doses up to 10 rag/day and is well tolerated; it is possible that a higher dose, if tolerated, might provide greater benefits. Objective: To determine the safety and tolerability of treatment with 15 or 20 rag/day donepezil in mild to moderate AD. Methods: This was a 2-center, randomized, double-blind, placebo-controlled study of higher dose donepezil (15 or 20 rag/day). Patients with mild to moderate AD (MMSE 10-26) currently receiving 10 mg/day donepezil were randomized to receive either higher dose donepezil