Dr. P.M. van Zyl Department of Pharmacology 2010

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

 Cholinergic hypothesis  Glutamate hypothesis  ?Combination: Glutamate an executor of neurodegenerative processes, and cholinergic neurones one of the victims.

 Olney and coworkers (1998): two phases:  1. over activation of NMDA receptors  damage of neurones bearing this receptor subtype - in particular GABAergic neurones  2. secondary hypofunctional state of NMDA receptors (  due to cell loss).  Loss of inhibitory (GABA) neurones in brain  further neurotoxicity due to disinhibition.

 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+.

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

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” is magnesium.

 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+.

 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.

 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

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

 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.

 Competitive antagonists of glutamate 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

 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.

 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 dose s: block 5-HT3 receptor-channels (?  cognition) and nicotinic receptor channels (?  glutamate release).

 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.

 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).

 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.

 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.

 Stuart A. Lipton 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 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