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NR2R antagonists prevent Aβ‑induced synaptic and has been reported to inhibit hippocampal LTP, [63]
dysfunction. Consistent with these findings, low disrupt cognitive flexibility, and impair memory and
[9]
concentrations of memantine have been shown to locomotor behaviors. [64,65] Interestingly, a comparison
target extrasynaptic NMDAR. [56] Both studies and between the effects of donepezil and memantine on
related reports suggest that Aβ oligomers disrupt spatial memory in the APP23 mouse model using a
glutamate uptake or trigger glutamate release from complex dry‑land maze test showed that donepezil
glial cells, thus increasing glutamate levels to induce treatment significantly improved moving time, whereas
synaptic dysfunction. memantine improved resting time, thus suggesting
that donepezil may influence memory acquisition and
BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS memantine influences memory retrieval. [66]
IN DEMENTIA
Donepezil administration increases dopamine and
AD is a neurodegenerative disorder associated norepinephrine levels in the dorsal hippocampus
not only with a decline in cognitive abilities, but and decreases extracellular norepinephrine and
also with frequent manifestation of noncognitive serotonin levels in the ventral hippocampus. [67]
symptoms (such as anxiety, depression, apathy, In contrast, memantine decreases dopamine and
and psychosis) and other conduct disorders that serotonin in the dorsal hippocampus and increases
impair daily living. [57] It has been proposed that the 3‑methoxy‑4‑hydrophenylglycol in the ventral
behavioral and psychological symptoms of dementia hippocampus. Although memantine is recognized
in AD patients are due to an imbalance of different as a moderate affinity, noncompetitive, reversible
neurotransmitters (ACh, dopamine, noradrenaline, NMDAR antagonist, it has been demonstrated
and serotonin) in specific brain regions responsible that memantine enhances synaptic transmission
for emotional activities (parahippocampal gyrus, in an mAChR‑dependent manner in the mouse
dorsal raphe, and locus coeruleus) and cortical hippocampus, [68] and may interact more potent with
hypometabolism. [58] cholinergic receptors than with NMDAR. [69] Acute
systemic or local administration of either memantine
There is increasing awareness that the cholinergic or donepezil significantly increases ACh levels in the
system plays a role in emotion and noncognitive neocortex and hippocampus of rats. [70]
behavior and may be involved in neuropsychiatric
symptoms of AD. [59,60] Other evidence indicates that EFFICACY OF DONEPEZIL AND MEMANTINE ON
monoamines, in addition to ACh, are also involved THE TREATMENT OF AD
in the pathogenesis of AD and other dementia
disorders. The increased activity and altered AChEIs are considered the standard treatment of the
serotonergic modulation as a result of dopaminergic mild‑to‑moderate stage of AD, [71] whereas memantine
neurotransmission are associated with agitated is suggested for moderate‑to‑severe AD patients. [72]
and aggressive behavior, respectively. [61] Chronic Clinically, donepezil at 10 mg/day significantly improves
administration of donepezil has been reported to cognitive, neuropsychiatric, and global function,
reduce the incidence of neuropsychiatric symptoms thus reducing caregiver burden. [62,72] Increasing the
in patients with mild to moderately severe AD. [62] daily dose to 23 mg/day was found to be safe and
Thus, the stimulation of monoaminergic activity tolerated in patients with moderate‑to‑severe AD. [73,74]
in conjunction with AChE activity may provide an Memantine has been found to improve global cognition,
effective treatment option for AD and accompanying functional communication, and some behavioral
psychiatric disorders. symptoms (agitation and aggression). [75,76] Interestingly,
donepezil and memantine also have differential
COMPARISON OF DONEPEZIL AND MEMANTINE behavioral effects: donepezil affects depression, anxiety,
and apathy whereas memantine mainly affects agitation,
It is well‑established that AChEIs inhibit the action aggression, and delusions. [77,78] A recent clinical review
of the ACh‑hydrolyzing enzyme AChE to boost ACh suggests that combination therapy with donepezil and
levels, and thus, alleviate disease symptoms associated memantine for AD could be safe and well‑tolerated
with the progressive loss of cholinergic function in AD. for moderate‑to‑severe AD. [79] However, there are no
In contrast, memantine acts at the NMDAR to lower significant benefits of the combination of donepezil
the pathologically increased tonic level of excitation and memantine over donepezil alone on cognitive
of the glutamatergic synapse at rest. Although function. [80] Thus, combination therapy may be more
AChEIs significantly improve learning and memory, effective in improving neuropsychiatric behaviors than
memantine behaves like other NMDAR antagonists cognition because of their complementary activity.

276 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 277