Symptomatological Effects of Memantine

1. Symptomatological Effects of Memantine

2. Long-Term Potentiation Technique in hippocampal slices Stimulating electrode Recording electrode CA1 CA3 DG Frankiewicz & Parsons, Neuropharmacology 1999

3. Memantine Counteracted Deficits in LTP Induced by Low Mg2+ Stimulation (100 Hz) Memantine completely restored LTP Control LTP MK-801 failed to restore LTP Deficit in LTP after Mg2+ removal 180 160 140 120 100 80 Control EPSP Amplitude (%) 0 20 40 60 80 Time (min) Frankiewicz & Parsons, Neuropharmacology 1999

4. Passive Avoidance Learning: Experimental Setting injection Reinforcement 2 shocks when entering the dark box Habituation Day 1 Training Day 2 Retention Test Day 3 Choice box (light) Start box (light) Test Parameters The latency to enter the dark box Choice box (dark) Zajaczkowski et al., Neuropharmacology 1997

5. Memantine Attenuated Learning Deficits Induced by NMDA Passive avoidance learning Control (300 sec) * * 100 80 60 40 20 0 Latency to enter the dark box (% of control) NMDA 25 mg/kg NMDA + Memantine 1,25 mg/kg NMDA + Memantine 2,5 mg/kg NMDA + Memantine 5 mg/kg * p < 0.05 versus NMDA Zajaczkowski et al., Neuropharmacology 1997

6. Memantine in an Animal Model for Neurodegenerative Dementia Implantation of mini-pump/ Infusion of memantine (s.c. 20 mg/kg/day) Radial maze learning4 trials/day for 12 days 1 week 4 days Symptomatological effects Quinolinic acid lesion of the entorhinal cortex Zajaczkowski et al., Eur J Pharmacol 1996

7. Memantine Did Not Restore Working Memory Memantine in an animal model for neurodegenerative dementia 0.4 0.3 0.2 0.1 0 Sham operated Lesion  Lesion + memantine Frequency of working memory errors * * 1 2 3 4 5 6 Blocks of 2 days * p < 0.05 versus sham operated for the whole learning period Zajaczkowski et al., Eur J Pharmacol 1996

8. Memantine Restored Reference Memory Memantine in an animal model for neurodegenerative dementia 0,50 0,45 0,40 0,35 0,30 0,25 Sham operated Lesion  Lesion + memantine Frequency of reference memory errors * 1 2 3 4 5 6 Blocks of 2 days * p < 0.05 versus lesion for the whole learning period Zajaczkowski et al., Eur J Pharmacol 1996

9. Summary • Long term potentiation is an in vitro correlate for memory formation. Memantine counteracted a deficit of long term potentiation induced by tonic NMDA receptor activation (increased background noise) • Memantine counteracted amnestic effects of continuous NMDA receptor stimulation (increased background noise) in the passive avoidance task • Memantine infusion (20 mg/kg/day, therapeutic serum levels) restored reference memory in rats with entorhinal cortex lesion Conclusion • Clinically relevant doses of memantine may produce symptomatological improvements in learning and memory under conditions of tonic NMDA receptor activation and neurodegeneration (e.g. in Alzheimer´s Disease)