Preclinical Data of Memantine

Memantine is an NMDA receptor antagonist that has been recently approved in EU for the treatment of moderate to severe Alzheimer’s disease. The NMDA receptor blocking property of this agent was recognized at the end of 80’s (Kornhuber et al., 1989), it’s precise mode of action such as voltage and use dependency was shown by Parsons et al., 1993.

Memantine restores impaired neuronal plasticity and improves learning

In order to test the signal-to-noise hypothesis, a model was selected that mimics several aspects of a hyperactive glutamatergic system and is associated with pathological activity and impaired synaptic plasticity.

• If NMDA receptors in hippocampal slices are overstimulated due to Mg²⁺ reduction or application of exogenous NMDA, synaptic plasticity such as LTP – the neuronal model of memory formation is indeed impaired (Zajaczkowski et al., 1997; Frankiewicz & Parsons, 1999). In these LTP experiments, synaptic plasticity impaired by glutamatergic hyperactivity – either in the presence of NMDA or lowered Mg²⁺ concentrations – was restored by memantine at concentrations equivalent to those known to improve cognition in Alzheimer’s patients. Interestingly, no improvement was seen with the high affinity antagonist dizocilpine, indicating again fundamental differences in its mode of action.
• Some of these experiments were confirmed in vivo since memantine attenuated impairment of passive avoidance learning produced by NMDA (Zajaczkowski et al., 1997).

Figure 6: Memantine attenuates NMDA-induced passive avoidance impairment. NMDA injected to rats produced amnesia (latency to enter the dark box is shorter) which was dose-dependently attenuated by memantine. In this test rats were trained to avoid a dark compartment connected with a footshock during training. When tested 24 hours later, control animals, but not NMDA injected (during training) animals avoided this compartment. Memantine dose-dependently attenuated the deficit produced by NMDA. Modified from (Zajaczkowski et al., 1997).

• Memantine also improved learning in rats with entorhinal cortex lesions which has some relevance to AD since this structure is affected in early stages of this disease (Braak et al., 1993). A few days after lesioning, minipumps containing memantine (20 mg/kg per day) were implanted subcutaneously and then rats were tested in a typical spatial learning task – the radial maze. Initially all lesioned groups showed a clear learning impairment, however after 9 days of testing (and parallel infusion) memantine-treated animals started to learn better reaching levels identical to non-lesioned animals (Zajaczkowski et al., 1996).
• Similarly, in moderately-aged rats memantine prolonged the duration of LTP in vivo and also showed a trend to improve memory retention in the Morris maze learning task (Barnes et al., 1996).
• Memantine also reversed learning impairment in the Morris water maze produced by a lesion (AF64A selective toxin) of the central cholinergic system (Bachurin et al., 2001). In the same test, in rats withdrawn from chronic ingestion of alcohol, memantine similarly ameliorated learning deficits (Lukoyanov & Paula-Barbosa, 2001).

Memantine prevents neuronal damage

Long term overactivation of NMDA receptors would be expected to lead to neuronal death. Thus, it seems clear that under such conditions antagonism of NMDA receptors should provide neuroprotection. Memantine has been tested against insults believed to contribute to the pathomechanism of Alzheimer's disease. Thus, memantine at therapeutically relevant doses (leading to plasma levels ca. 1 µM) provided in vivo protection from a variety of toxic conditions such as β-amyloid, inflammation, inhibition of mitochondrial function, and decrease in blood flow to the brain (Table 1). All of these factors have been implicated in the pathomechanism of Alzheimer’s disease. Thus, because the pathomechanism of Alzheimer’s disease involves multiple contributing factors, a drug like memantine should be a particularly effective disease modifying agent. This feature clearly distinguishes memantine from cholinesterase inhibitors which are not expected to inhibit disease progression.

Examples of neuroprotective effects of memantine in various conditions that may be relevant for the pathomechanism of Alzheimer’s disease.

3-NP – 3-nitropropionic acid (mitochondrial toxin); LPS – lipopolysaccharide – an element of wall of Gram negative bacteria.