Memantine in Dementia Therapy – Current Findings and Possible Future Applications

Mechanism of Action

Disruption of glutamatergic neurotransmission, especially at NMDA receptors, is associated with the development and gradual progression of neurodegenerative dementia. These receptors play an important role in the processes of memory and learning in the central nervous system (CNS).

Memantine is a non-competitive antagonist of NMDA receptors that modulates the response to pathologically elevated levels of glutamate in the synaptic cleft, which can lead to neuronal dysfunction. The advantage of the drug is its low affinity for these receptors, which prevents prolonged blockade and the occurrence of side effects such as memory and concentration disorders. Another advantage is that memantine's interaction with the receptor occurs only in cases of its pathological activation, as is the case in Alzheimer's disease.

Currently, it is a commonly prescribed drug in the treatment of Alzheimer's disease, often in combination with acetylcholinesterase inhibitors, as cholinergic dysfunction also plays an important role in the pathophysiology of the disease.

Study Results

Preclinical studies have identified a number of positive effects of memantine in the CNS as well as in metabolism. Its administration in preclinical models led to an improvement in Alzheimer’s disease neuropathology through NMDA receptor inhibition, increased levels of brain-derived neurotrophic factor (BDNF), number of synapses, reduced neuroinflammation and oxidative stress, improved memory, and reduction in amyloid levels and β-secretase 1. In mouse models, memantine also demonstrated effects on reducing microglial activity and other interesting effects.

Equally interesting are new findings on memantine's impact on metabolism. Recent studies suggest a link between type 2 diabetes and Alzheimer's disease. Disruption of glucose metabolism in neurodegenerative disease is referred to as type 3 diabetes, characterized by alterations in insulin receptors in the hippocampus. The beneficial metabolic effects of memantine are likely due to the inhibition of peripheral NMDA receptors in the pancreas and the blockade of hypothalamic amyloid-beta levels. Thus, it appears that Alzheimer's disease is a cognitive disorder associated with central and peripheral metabolic dysfunction, and the administration of memantine along with antidiabetics could be a potential strategy to slow its progression.

Although numerous clinical studies have shown the positive effect of memantine on slowing the disease progression, especially in combination with acetylcholinesterase inhibitors or vitamin D, current results do not yet provide satisfactory data on clinical efficacy, particularly from the perspective of disease curability. Possible explanations include late initiation of memantine in the field of advanced and irreversible neuronal damage. Another potential explanation is that memantine needs to be administered with other medications to potentiate its effect on slowing and preventing the disease. Additionally, even if it is effective in treating neuronal damage, it remains uncertain whether these neurons stay active afterward.

Although memantine is a drug with a fairly long history, it is still a subject of research, and further studies are being conducted to test its potential effect in the treatment of other disorders. Due to its influence on BDNF, it could be used in the treatment of alcoholism or Parkinson's disease. Positive effects have also been observed in patients with depression, schizophrenia, Huntington's disease, or multiple sclerosis.

Conclusion

Alzheimer's disease is an incurable neurodegenerative disease. The NMDA receptor antagonist memantine is used in its treatment; its administration in preclinical studies is associated with a number of benefits, including the prevention of neuron death caused by glutamate excitotoxicity. The administration of memantine, especially in combination with acetylcholinesterase inhibitors, contributes to slowing the progression of the disease and improving cognitive functions.

Given the incurability of the disease, memantine represents one of the few options for its current management. Experimentally, it has also been shown to have a beneficial effect on pathologically altered glucose metabolism in Alzheimer's disease through the influence on the hypothalamus and pancreas, which could, in combination with antidiabetics, be a promising strategy in delaying the disease's progression in the future.

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Source: Folch J., Busquets O., Ettcheto M. et al. Memantine for the treatment of dementia: a review on its current and future applications. J Alzheimers Dis 2018; 62 (3): 1223–1240, doi: 10.3233/JAD-170672.