Page 10 - JCBP-1-2

Journal of Clinical and
Basic Psychosomatics Melatonin for dementia therapy

MT1/MT2 may act as potential targets for treatments of induced AD rats . Another study reported that melatonin
[62]
depression . Research has shown that melatonin produces reduces amyloid-β accumulation, improves short-
[53]
an antidepressant-like effect by interacting with dopamine term memory , reduces memory impairment and tau
[65]
receptors . Furthermore, melatonin has been shown to be aggregation, and improves diabetes mellitus, which is a
[54]
closely related to post-traumatic stress disorder (PTSD) and risk factor for the development of AD, in a streptozotocin-
[66]
[55]
stress-related disorders associated with dementia , while induced AD rat model . Other researches have also
ramelteon, a melatonin receptor agonist, has been reported found that D-penicillamine regulates ADAM10 expression
to improve PTSD symptoms in fatty acid-binding protein through the MT1 receptor and downstream PKA/ERK/
3 (FABP3) null mice . FABP is a protein that is highly CREB pathway and may improve the cognitive ability of
[56]
expressed in the central nervous system and is associated APP/PS1 mice by reducing Aβ generation . Together,
[67]
with dopamine 2 (D2) long isoform (D2L) receptors . these studies suggest that melatonin may ameliorate
[57]
Administration of melatonin has been shown to increase amyloid-β aggregation and cognitive impairment in
the affinity of D2 dopamine receptors in rat brains . It has AD through receptor-mediated and non-receptor-
[58]
also been suggested that melatonin may affect the function mediated pathways. It has been hypothesized that the
of D2L receptors in PTSD through FABP. CaMKII may melatonin-mediated amelioration of AD could be effected
[68]
also play a role in dopamine and glutamate signaling . through the regulation of cholesterol , cholinergic
[50]
[69]
[19]
[70]
Research has shown that CaMKIIα interacts with D2 system , neurogenesis , insulin, and mitochondrial
[71]
receptors and binds to D2 receptors in vitro . Studies dysfunction .
[59]
have also found that CaMKII and D2 receptors contribute Many proteins linked to the production of amyloid-β
[60]
to the drug reward system , and it is suggested that have a putative calmodulin-binding domain, thus
CaMKII acts on the reward system through D2 receptors. contributing to the hypothesis suggesting that calmodulin
It has also been reported that inhibition of CaMKII activity is critically involved in AD . In connection with
[72]
in the amygdala, which is involved in reward learning, may this hypothesis, calcineurin (CaN), which is activated
inhibit the memory formation of inhibitory avoidance . downstream of soluble amyloid-β aggregates, is thought
[61]
Thus, it is possible that the antidepressant or anxiety effects to play a pivotal role in AD . A previous study reported
[73]
of melatonin may be mediated through the activation of that melatonin exhibits neuroprotective effects when
dopamine receptors, which are induced by CaMKII. oxidative damage-induced cell death occurs by preventing
These findings suggest that melatonin may act as a the CaN-activated nuclear translocation of activated T-cell
[74]
therapeutic agent for dementia through MT1/2 receptor- nuclear factors in human neuroblastoma SH-SY5Y cells .
mediated and non-mediated mechanisms, dopamine and Interestingly, CaN and CaMKII are believed to have
NMDA receptor-mediated mechanisms, and through opposite functions in dendritic spines: CaMKII activity
2+
CaM, CaMKII, ERK, and AMK (Figure 1 and Table 1). promotes long-term synaptic potentiation after a Ca
influx through NMDA-type glutamate receptors, and CaN
3. Involvement of melatonin in the responds to the reduced Ca influx by inducing long-term
2+
[75]
treatment of major types of dementia depression through the same receptors . It has also been
suggested that CaN-dependent dephosphorylation inhibits
3.1. Involvement of melatonin in the treatment of AD CaMKII-mediated phosphorylation, and this inhibition
Various studies have shown that melatonin plays a major increases phospho-CaMKII, thereby stimulating CaMKII-
[76]
role in reducing the production and aggregation of dependent cellular actions . However, melatonin may
amyloid-β and in the treatment of AD. Melatonin is known suppress CaN through CaMKII, thereby promoting
to regulate the expression of BACE1, APP, and ADAM10 long-term potentiation (LTP), improving learning and
genes through its antioxidant action and receptor-mediated memory functions, and exhibiting a neuroprotective
action and may also alleviate the amyloid-β -induced effect that suppresses AD. CaMKII promotes the release
42
[77]
reduction of Pin1 and suppress GSK expression to inhibit of acetylcholine ; however, melatonin is expected to be
the promotion of amyloid-β production [62,63] . Research a new symptomatic drug for AD that improves memory
has also demonstrated that long-term oral melatonin and cognition through a mechanism different from that of
administration has an implication on amyloid-β cholinesterase inhibitors.
transport and autophagy and reduces the accumulation of AD is associated with various BPSDs. Research has
amyloid-β . In a previous study, melatonin was found to shown that depression may worsen AD pathology in the
[64]
ameliorate cognitive impairment, amyloid-β production, hippocampus , while melatonin has been reported to
[78]
tau aggregation, and decreased dopamine transporter ameliorate depression and anxiety in AD mice . Studies
[52]
expression in the hippocampus of methamphetamine- have reported that melatonin and ramelteon improve sleep
Volume 1 Issue 2 (2023) 4 https://doi.org/10.36922/jcbp.1174