Memantine: Targeting glutamate excitotoxicity in Alzheimer's disease and other dementias

Abstract

The management of dementia has changed since the development of new antidementia drugs. The benefits observed in Alzheimer's disease (AD) with selective cholinergic transmission treatments are mainly symptomatic, without clear evidence of neuroprotection. The hypothesis that glutamate-mediated neurotoxicity is involved in the pathogenesis of AD is finding increasingly more acceptance in the scientific community. Glutamate receptors are overactive, and N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential for the treatment of AD and other neurological disorders. Memantine is a noncompetitive NMDA antagonist that is considered a neuroprotective drug. Memantine's capacity has been demonstrated in preclinical studies, and it is considered a useful symptomatic treatment for AD. Memantine has been shown to benefit cognition, function, and global outcome in patients with moderate to severe AD, and it is currently approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe AD. Recently, memantine has also demonstrated efficacy in the initial stages of AD, although FDA authorization is pending. This review highlights the important pharmacological and clinical aspects of memantine, as well as some basic mechanisms mediating glutamatergic neurodegeneration.

Statin inhibits kainic acid-induced seizure and associated inflammation and hippocampal cell death

“…Excitotoxicity is a major pathological mechanism underlying acute and delayed neuronal death induced by prolonged ischemia, traumatic brain and spinal cord injuries and Alzheimer's disease as well as epilepsy/seizure [19,25,43]. Therefore, studies have been focused on the reduction of glutamate accumulation in synaptic clefts and/or on the inhibition of glutamateinduced neuronal excitation for prevention of neuronal cell death under various neurological disease conditions.…”

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

“…Release and metabolism of AA through the phospholipase A 2 (PLA 2 )/ PTGS pathway is increased during excitotoxicity [12], a process that involves the over activation of brain excitatory neurotransmission. Kainic acid (KA), the prototypic excitotoxin, binds to the KA receptors in the brain and induces seizures that result in inflammation, oxidative damage and neuronal death, processes that have been implicated in neurological, neurodegenerative and psychiatric diseases [16,20,40,49,52,66,68,71,72]. Although it has been demonstrated that PTGS plays a role in excitotoxicity, the distinct role of the two PTGS isoforms has not been fully established.…”

Influx Transport of Cationic Drug at the Blood–Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants

“…Several cationic drugs, such as memantine, propranolol and clonidine, have recently been reported to exert a neuroprotective effect in the brain and retina, [18][19][20] and these reports support the substantial contribution of the study of cationic drug transport at the BRB in developing future treatments for retinal disease. In the in vivo transport study of verapamil in rats, the apparent influx clearance of [ 3 H] verapamil (K in, verapamil, retina ) was calculated to be 614 µL/(min·g retina), which was much greater than that of paracellular transport markers, 21) supporting the facilitative influx transport system The correlation of an initial uptake rate (log V) of compounds undergoing carrier-mediated transport (A) and passive diffusion (B) in TR-iBRB2 cells with the RUI in rats was studied, and a linear relationship described by Eqs.…”

“…Because of the neuroprotective effects of cationic drugs, as previously reported, [18][19][20] the influx transport system of cationic drugs at the BRB is expected to be helpful in the delivery of neuroprotectants into the retina. Among such cationic neuroprotectants, propranolol reduces the expression of vascular endothelial growth factor (VEGF), and clonidine induces basic fibroblast growth factor (bFGF) to exert a neuroprotective effect.…”