Memantine and Neuroprotection

1. Memantine and Neuroprotection Dr. P.M. van Zyl Department of Pharmacology 2010

2. Dementia • A major cause of disability and death worldwide. • Economists: treatment of dementia will consume the entire gross national product of western countries by 2050. • Alzheimer’s disease: leading cause of dementia, fourth in mortality in the US.

3. Alzheimer’s Disease • Cholinergic hypothesis • Glutamate hypothesis • ?Combination: Glutamate an executor of neurodegenerative processes, and cholinergic neurones one of the victims.

4. NEUROPATHOLOGY IN ALZHEIMER’S DEMENTIA • Olney and coworkers (1998): two phases: • 1. over activation of NMDA receptors damage of neurones bearing this receptor subtype - in particular GABAergicneurones • 2. secondary hypofunctional state of NMDA receptors ( due to cell loss). • Loss of inhibitory (GABA) neurones in brain further neurotoxicity due to disinhibition.

6. Glutamate • Main excitatory neurotransmitter • Rapidly convey sensory information, motor commands • Thoughts and memories • Most neurons and glia contain high [glutamate]. • Released for milliseconds to communicate with other neurons via synaptic endings • 3 classes of ionotropic channels: AMPA receptors, kainate receptors and NMDA receptors. • NMDARs most permeable to Ca2+.

7. Glutamatergic synapse Schematic presentation of the glutamatergic synapse and major ionotropic glutamate receptors – AMPA and NMDA. NMDA channel activated for only brief periods due to relief of Mg2+ blockade, which occurs after cation influx into the neuron via AMPAsensitive glutamate receptor channels

8. Synaptic plasticity in CNS : detection of relevant signal over existing background noise  long lasting alteration in synaptic strength. NMDA receptors plays central role in such alterations and an endogenous “noise suppressant” ismagnesium.

9. Glutamate • Powerful: • Too much, too long  excite cells to death • Excessive activation of NMDAR  free radicals and activation of proteolytic processes cell injury/death. • Cleared by glutamate transporters • Ionic homeostasis energy dependent • Energy compromised neurons become depolarized (more positively charged) relieves normal block of NMDARcoupled channels by Mg2+.

10. Excitotoxicity • Glutamate-related neuronal cell injury and death • occurs in part because of overactivation of N-methyl-d-aspartate(NMDA)-sensitive glutamate receptors, permitting excessive Ca2+ influx through the receptor’s associated ion channel.

11. Excitotoxicity play a role in • Alzheimer’s disease • Parkinson’s disease • Huntington’s disease • HIV-associated dementia • Multiple sclerosis • Amyotrophic lateral sclerosis (ALS) • Neuropathic pain • Glaucoma • Stroke, CNS trauma and seizures

12. Glutamate and glycine bind  cell is depolarized to remove Mg2+ block NMDAR channel opens  influx of Ca2+ and Na+.

13. NMDAR antagonists • Potential therapeutic benefit in range of neurological disorders. • Must leave normal NMDAR function relatively intact • LTP in hippocampus: cellular–electrophysiological correlate of learning and memory formation. • Reticular activating system in brainstem: if compromised: drowsiness, even coma.

14. Clinically tolerated antagonists • Competitive antagonists ofglutamate or glycine block normal function, not pathological function. • Displaced from receptor by the high local concentrations of glutamate or glycine that can exist under excitotoxic conditions. • Neuroprotective dose of MK-801: coma • Phencyclidine “Angel Dust” hallucinations • Ketamine: narcosis

15. Clinically tolerated antagonists • Theoretic solution: ‘uncompetitive’ antagonist. (An inhibitor whose action is contingent on prior activation of the receptor by the agonist.): blocks higher concentrations of agonist to a greater degree than lower concentrations of agonist.

16. Memantine • Relatively low-affinity, open-channel blocker — only enter channel when it is opened by agonist. • Relatively fast off-rate: prevents accumulation in ion channels and interfering with subsequent normal synaptic transmission. • Neuroprotection with minimal adverse effects. • Reported SE: • occasional akathesia, • rare slight dizziness at higher dosages. • At high doses: block 5-HT3 receptor-channels (? cognition) and nicotinic receptor channels (? glutamate release).

17. Memantine: Neuroprotection • Observed in cultures and animal models • Example: Rat model of stroke, memantinebrain damage by approximately 50%. • Proving neuroprotection in humans • Minimal adverse effects. Rare: dizziness, restlessness/ agitation (@ higher doses: 40–60 mg/ day). • Memantine work better for severe conditions. • Neuropathic pain • Alzheimer’s disease: FDA approval for moderate-to-severe disease.

18. Memantine • Initial stage: disease progression + symptom improvement • Later: NMDA receptors on functional neurones fully preserved ( moderate affinity antagonist). • Zajaczkowski et al., 1997: in tonic activation of NMDA receptors, memantine can reverse deficits in synaptic plasticity, both at neuronal (LTP) and behavioural (learning) level • Significant improvement in: cognitive processes, daily activities and self care (Ditzler, 1991; Görtelmeyer and Erbler, 1992; Winblad and Poritis, 1999).

20. CONCLUSIONS • Agents such as memantine which mimic some of the features of the endogenous antagonist magnesium may be an optimal treatment combining both neuroprotective activity with symptomatological improvement.

21. Summary • Memantine, an “un-competitive” NMDA antagonist. • Rationale for use: excitotoxicity as a pathomechanism of neurodegenerative disorders. • Memantine acts as a neuroprotective agent • Promising for treatment of dementias, particularly Alzheimer’s disease. • Combined with acetylcholinesterase inhibitors(mainstay of current symptomatic treatment of Alzheimer’s disease). • Therapeutic potential in other CNS disorders: stroke, CNS trauma, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, drug dependence and chronic pain.

22. References • Stuart A. Lipton. 2006. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond Nature Reviews Drug Discovery | AOP, 20. • W. Danysz, C.G. Parsons, H-J Möbius, A.Stöffler and G.Quack. 2000. Neuroprotective and Symptomatological Action of Memantine Relevant for Alzheimer’s Disease – A Unified Glutamatergic Hypothesis on the Mechanism of Action. Neurotoxicity Research, Vol. 2. pp. 85-97.