- Email: [email protected]
P1-454
Poster Presentations P1 Background: Intracerebroventricular (ICV) injection of streptozotocin (STZ) in rats is followed by long-term and progressive deficits in learning, memory, and cognitive performance in rats that is somewhat similar to sporadic Alzheimer’s disease (SAD). Epidemiological studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) could delay or slow the clinical expression of SAD. Objective(s): Therefore, the beneficial effect of mefenamic acid (MA) was investigated on ICV STZ-induced learning, memory, and cognitive impairment in male rats. Methods: For this purpose, rats were injected with ICV STZ bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats received MA (30 mg/kg/day, i.p.) starting from day 5 post-surgery for two weeks. The learning and memory performance was assessed using passive avoidance paradigm, and for spatial cognition evaluation, radial eight-arm maze (RAM) task was used. Results: It was found out that MA-treated STZ-injected rats show higher correct choices and lower errors in RAM than vehicle-treated STZ-injected rats. In addition, MA administration significantly attenuated learning and memory impairment in treated STZ-injected group in passive avoidance test. Conclusions: These results demonstrate MA efficacy against cognitive deficits as well as learning and memory impairment caused by ICV injection of STZ in rats and its potential in the treatment of some neurodegenerative disorders including SAD. P1-454
THE EFFECT OF CHRONIC ADMINISTRATION OF WITHANIA SOMNIFERA ON LEARNING AND MEMORY DEFICITS OF DIABETIC RATS
Mehrdad Roghani, Mohsen Khalili, Fatemeh Mahdavi, Shahed University, Tehran, Iran (Islamic Republic of). Contact e-mail: [email protected] Background: Diabetes mellitus (especially type I) is accompanied with disturbances in learning, memory, and cognitive skills in the human society and experimental animals. Currently, pathological studies have suggested that diabetes is one of the risk factors for senile dementia of Alzheimer’s type. Objective(s): Considering the potential anti-diabetic effect of the medicinal plant Withania somnifera (ashwagandha) and the augmenting effect of its consumption on the memory and mental health, therefore, this research study was conducted to evaluate the effect of chronic oral administration of ashwagandha root on learning and memory in diabetic rats using passive avoidance test. Methods: For this purpose, male Wistar diabetic rats were randomly divided into control, ashwagandha-treated control, diabetic, and ashwagandha-treated diabetic groups. Ashwagandha treatment continued for 1 to 2 months. For induction of diabetes, streptozotocin was injected i.p. at a single dose of 60 mg/kg. Serum glucose level was determined before the study and at 4th and 8th weeks after the experiment. In addition, for evaluation of learning and memory, initial latency (IL) and step-through latency (STL) were determined after 1 and 2 months using passive avoidance test. Results: It was found out that one- and two-month administration of ashwagandha root at a weight ratio of 1/15 has not any significant hypoglycemic effect in treated control and diabetic groups. Furthermore, there was a significant increase (p⬍0.05) in IL in diabetic and ashwagandha-treated diabetic groups after two months as compared to control group. In this respect, there was no significant difference between diabetic and ashwagandha-treated diabetic groups. In addition, STL significantly increased in ashwagandha-treated control group after 1 (p⬍0.01) and 2 (p⬍0.05) month in comparison with control group. On the other hand, STL significantly decreased (p⬍0.05) in diabetic group and significantly increased (p⬍0.05) in ashwagandha-treated diabetic group as compared to control group after two months. Conclusions: In summary, chronic oral administration of ashwagandha root could enhance the consolidation and recall capability of stored information in control and diabetic animals.
P1-455
S231 META-ANALYSIS OF NEUROPSYCHIATRIC INVENTORY (NPI) DOMAINS IN THREE 6MONTH TRIALS OF MEMANTINE IN MODERATE TO SEVERE AD
Jeffrey L. Cummings1, Jason T. Olin2, 1University of California, Los Angeles, Los Angeles, CA, USA; 2Forest Research Institute, Jersey City, NJ, USA. Background: Memantine, a moderate affinity, uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is approved in the U.S. and in Europe for the treatment of moderate to severe Alzheimer’s disease (AD). Objective: To assess the effects of memantine on behavioral disturbances in AD, an individual study meta-analysis from three largescale, randomized, placebo-controlled clinical trials was performed. Methods: NPI total score and individual domains from three, six-month memantine trials in moderate to severe AD patients were analyzed (MEM-MD-01, van Dyck et al, in preparation; MEM-MD-02, Tariot et al., 2004; MRZ 90001-9605, Reisberg et al., 2003). All trials were randomized, double-blind, parallel-group designs comparing memantine (10 mg b.i.d.) to placebo. MEM-MD-02 allowed concomitant donepezil therapy (6 months, stable for ⱖ3 months). Standardized mean differences (SMD) were calculated using fixed-effect models; random effects models were used when evidence of heterogeneity was observed (Chi2 Pⱕ .10). Analyses were based on Intention-to-Treat populations using a last observation carried approach for replacement of missing values. Results: Change from baseline on NPI total score at study endpoint for each trial revealed a statistically significant advantage of memantine over placebo in the MEM-MD-02 study only (P⫽.002). When data from all three trials were combined and analyzed, the NPI total score showed a homogeneous effect size in favor of memantine treatment (Chi2⫽3.32, P⫽.19; SMD⫽-0.17 [95%CI-0.30,-0.04], P⫽.01). Additionally, several NPI domains demonstrated statistically significant treatment differences in favor of memantine and all were homogeneous: delusions (Chi2⫽2.33, P⫽.31; SMD⫽-0.14 [95%CI0.27, -0.02], P⫽.03), agitation/aggression (Chi2⫽2.48, P⫽.29; SMD⫽0.24 [95%CI-0.37,-0.11], P⫽.0003), and irritability/lability (Chi2⫽3.49, P⫽.17; SMD⫽ -0.13 [95%CI -0.26, 0.0], P⫽.05). Heterogeneity was seen on hallucinations and depression/dysphoria. Conclusions: These findings suggest that memantine treatment of 6-months in duration can provide a reduction in specific behavioral disturbances in patients with moderate to severe AD, including agitation/aggression, delusions, and irritability/lability. P1-456
THE EFFECT OF MEMANTINE ON DISTINCT BEHAVIOR SYNDROMES IN MODERATE TO SEVERE AD PATIENTS
Jeffrey L. Cummings1, Jason T. Olin2, 1University of California, Los Angeles, Los Angeles, CA, USA; 2Forest Research Institute, Jersey City, NJ, USA. Contact e-mail: [email protected] Background: In a previously reported 24-week placebo-controlled, double-blind clinical trial in moderate to severe AD patients on concomitant donepezil treatment, memantine-treated patients performed significantly better on the Neuropsychiatric Index (NPI) than placebo-treated patients. Objective(s): The current study is a post hoc analysis in which NPI individual items were grouped into clusters to determine whether memantine has specific effects on one or more clusters. Memantine is a moderate affinity, uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist approved in the U.S. and in Europe for moderate to severe AD. Methods: Behavioral clusters were defined as follows: Mood (depression/dysphoria, anxiety, irritability/lability, night-time behavior disturbances, appetite/eating change), Psychosis (delusions, hallucinations, agitation/aggression), Frontal (euphoria/elation, disinhibition), or Other (apathy, aberrant motor behavior). A positive response for each cluster was defined as no net change or net improvement on the NPI items constituting the cluster. P values were based upon a CMH test controlling for study center. Results:
THE EFFECT OF CHRONIC ADMINISTRATION OF WITHANIA SOMNIFERA ON LEARNING AND MEMORY DEFICITS OF DIABETIC RATS
Mehrdad Roghani, Mohsen Khalili, Fatemeh Mahdavi, Shahed University, Tehran, Iran (Islamic Republic of). Contact e-mail: [email protected] Background: Diabetes mellitus (especially type I) is accompanied with disturbances in learning, memory, and cognitive skills in the human society and experimental animals. Currently, pathological studies have suggested that diabetes is one of the risk factors for senile dementia of Alzheimer’s type. Objective(s): Considering the potential anti-diabetic effect of the medicinal plant Withania somnifera (ashwagandha) and the augmenting effect of its consumption on the memory and mental health, therefore, this research study was conducted to evaluate the effect of chronic oral administration of ashwagandha root on learning and memory in diabetic rats using passive avoidance test. Methods: For this purpose, male Wistar diabetic rats were randomly divided into control, ashwagandha-treated control, diabetic, and ashwagandha-treated diabetic groups. Ashwagandha treatment continued for 1 to 2 months. For induction of diabetes, streptozotocin was injected i.p. at a single dose of 60 mg/kg. Serum glucose level was determined before the study and at 4th and 8th weeks after the experiment. In addition, for evaluation of learning and memory, initial latency (IL) and step-through latency (STL) were determined after 1 and 2 months using passive avoidance test. Results: It was found out that one- and two-month administration of ashwagandha root at a weight ratio of 1/15 has not any significant hypoglycemic effect in treated control and diabetic groups. Furthermore, there was a significant increase (p⬍0.05) in IL in diabetic and ashwagandha-treated diabetic groups after two months as compared to control group. In this respect, there was no significant difference between diabetic and ashwagandha-treated diabetic groups. In addition, STL significantly increased in ashwagandha-treated control group after 1 (p⬍0.01) and 2 (p⬍0.05) month in comparison with control group. On the other hand, STL significantly decreased (p⬍0.05) in diabetic group and significantly increased (p⬍0.05) in ashwagandha-treated diabetic group as compared to control group after two months. Conclusions: In summary, chronic oral administration of ashwagandha root could enhance the consolidation and recall capability of stored information in control and diabetic animals.
P1-455
S231 META-ANALYSIS OF NEUROPSYCHIATRIC INVENTORY (NPI) DOMAINS IN THREE 6MONTH TRIALS OF MEMANTINE IN MODERATE TO SEVERE AD
Jeffrey L. Cummings1, Jason T. Olin2, 1University of California, Los Angeles, Los Angeles, CA, USA; 2Forest Research Institute, Jersey City, NJ, USA. Background: Memantine, a moderate affinity, uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is approved in the U.S. and in Europe for the treatment of moderate to severe Alzheimer’s disease (AD). Objective: To assess the effects of memantine on behavioral disturbances in AD, an individual study meta-analysis from three largescale, randomized, placebo-controlled clinical trials was performed. Methods: NPI total score and individual domains from three, six-month memantine trials in moderate to severe AD patients were analyzed (MEM-MD-01, van Dyck et al, in preparation; MEM-MD-02, Tariot et al., 2004; MRZ 90001-9605, Reisberg et al., 2003). All trials were randomized, double-blind, parallel-group designs comparing memantine (10 mg b.i.d.) to placebo. MEM-MD-02 allowed concomitant donepezil therapy (6 months, stable for ⱖ3 months). Standardized mean differences (SMD) were calculated using fixed-effect models; random effects models were used when evidence of heterogeneity was observed (Chi2 Pⱕ .10). Analyses were based on Intention-to-Treat populations using a last observation carried approach for replacement of missing values. Results: Change from baseline on NPI total score at study endpoint for each trial revealed a statistically significant advantage of memantine over placebo in the MEM-MD-02 study only (P⫽.002). When data from all three trials were combined and analyzed, the NPI total score showed a homogeneous effect size in favor of memantine treatment (Chi2⫽3.32, P⫽.19; SMD⫽-0.17 [95%CI-0.30,-0.04], P⫽.01). Additionally, several NPI domains demonstrated statistically significant treatment differences in favor of memantine and all were homogeneous: delusions (Chi2⫽2.33, P⫽.31; SMD⫽-0.14 [95%CI0.27, -0.02], P⫽.03), agitation/aggression (Chi2⫽2.48, P⫽.29; SMD⫽0.24 [95%CI-0.37,-0.11], P⫽.0003), and irritability/lability (Chi2⫽3.49, P⫽.17; SMD⫽ -0.13 [95%CI -0.26, 0.0], P⫽.05). Heterogeneity was seen on hallucinations and depression/dysphoria. Conclusions: These findings suggest that memantine treatment of 6-months in duration can provide a reduction in specific behavioral disturbances in patients with moderate to severe AD, including agitation/aggression, delusions, and irritability/lability. P1-456
THE EFFECT OF MEMANTINE ON DISTINCT BEHAVIOR SYNDROMES IN MODERATE TO SEVERE AD PATIENTS
Jeffrey L. Cummings1, Jason T. Olin2, 1University of California, Los Angeles, Los Angeles, CA, USA; 2Forest Research Institute, Jersey City, NJ, USA. Contact e-mail: [email protected] Background: In a previously reported 24-week placebo-controlled, double-blind clinical trial in moderate to severe AD patients on concomitant donepezil treatment, memantine-treated patients performed significantly better on the Neuropsychiatric Index (NPI) than placebo-treated patients. Objective(s): The current study is a post hoc analysis in which NPI individual items were grouped into clusters to determine whether memantine has specific effects on one or more clusters. Memantine is a moderate affinity, uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist approved in the U.S. and in Europe for moderate to severe AD. Methods: Behavioral clusters were defined as follows: Mood (depression/dysphoria, anxiety, irritability/lability, night-time behavior disturbances, appetite/eating change), Psychosis (delusions, hallucinations, agitation/aggression), Frontal (euphoria/elation, disinhibition), or Other (apathy, aberrant motor behavior). A positive response for each cluster was defined as no net change or net improvement on the NPI items constituting the cluster. P values were based upon a CMH test controlling for study center. Results: