Personalized Medicine Universe xxx (2013) 1e4

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Personalized Medicine Universe
journal homepage: www.elsevier.com/locate/pmu

Review

DL-/PO-phosphatidylcholine may shed light on the treatment of Alzheimer
dementia
Tomoyuki Nishizaki a, *, Takeshi Kanno a, Akinobu Gotoh bab

Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan
Laboratory of Cell and Gene Therapy, Institute for Advanced Medical Sciences, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japana r t i c l e i n f oa b s t r a c t

Article history:
Received 8 November 2012
Accepted 18 March 2013

Purpose: Thus far, no promising drug for Alzheimer disease has been developed. Previously, we documented the beneﬁcial effects of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DL-PC) and/or 1palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (PO-PC), which enhanced learning and memory abilities and improved cognitive disorders in both animals and humans. The present study reviews theusefulness of DL- and PO-PC for the treatment of Alzheimer dementia.
Study section and results: The anti-dementia effect of DL-PC, PO-PC, or DL-PC plus PO-PC was assessed inpatients with cognitive decline and dementia by using the Mini-Mental State Examination (MMSE) test.
The initial MMSE score for the patients was 17.4  0.3; however, 1 month after taking DL- and/or PO-PC
the score increased to over 20, corresponding to normal cognitive functions, and the effect was still
evident in some subjects 5 years after taking DL- and/or PO-PC. Among the subjects in this study, 20patients with Alzheimer disease had taken donepezil hydrochloride for more than 1 year. The MMSE
score for those 20 patients was 11.8  1.1, and the score signiﬁcantly improved to 19.9  1.6 one year after
stopping donepezil medication and instead taking DL- and PO-PC.
Conclusion: The results of the present study demonstrate that DL-/PO-PC could be an effective therapeutic agent for Alzheimer dementia.
Copyright Ó 2013, International Society of Personalized Medicine. Published by Elsevier B.V. All rights
reserved.

Keywords:Phosphatidylcholine
Donepezil hydrochlorideAlzheimer dementia
MMSE

1. Introduction
Alzheimer disease is a tragic disease that is characterized bysevere dementia in association with rapidly progressing brain atrophy. Several therapeutic approaches for Alzheimer disease havebeen attempted, yet no promising drug has resulted. Acetylcholinesterase inhibitors (AChEIs), such as donepezil, galantamine, andrivastigmine, have been clinically used for Alzheimer disease, but
their effectiveness is limited only to an alleviation of Alzheimer
disease symptoms [1]. Similarly, there is no evidence that memantine, a partial antagonist of N-methyl-D-aspartate (NMDA) receptor, is more effective than AChEIs in treating Alzheimer disease
symptoms [1].

Abbreviations: DL-PC, 1,2-dilinoleoyl-sn-glycero-3-phosphocholine; PO-PC, 1palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; MMSE, Mini-Mental State Examination; ACh, acetylcholine; AChEIs, acetylcholinesterase inhibitors; NMDA, Nmethyl-D-aspartate; PLA2, phospholipase A2; PLD, phospholipase D; nACh, nicotinic
ACh; LTP, long-term potentiation; LTD, long-term depression; AMPA, a-amino-3hydroxy-5-methyl-4-isoxazole propionic acid.
* Corresponding author. Tel.: þ81 798 45 6397; fax: þ81 798 45 6649.
E-mail address: tomoyuki@hyo-med.ac.jp (T. Nishizaki).

Accumulating evidence has pointed to the critical role of lipids
in cognitive functions. The present study investigated whether thephospholipids 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) and/or 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine(PO-PC) are useful for the treatment of Alzheimer dementia.

2. Implication of DL- and/or PO-PC in cognitive functions
Phospholipids, which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol,
are members of cell membrane components. Phosphatidylcholine
is hydrolyzed into lysophosphatidylcholine and cis-unsaturated
free fatty acids, such as arachidonic, oleic, linoleic, linolenic, anddocosahexaenoic acid, by phospholipase A2 (PLA2) [2] (Fig. 1).
Alternatively, phosphatidylcholine can be hydrolyzed into choline
and phosphatidic acid by phospholipase D (PLD), followed byfurther hydrolysis of phosphatidic acid into lysophosphatidic acidand cis-unsaturated free fatty acids by PLA2 [2] (Fig. 1). Amongother effects, these hydrolysis products interact with nicotinic ACh(nACh) receptors. For example, cis-unsaturated free fatty acids
potentiate nACh receptor responses to facilitate hippocampal

2186-4950/$ e see front matter Copyright Ó 2013, International Society of Personalized Medicine. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.pmu.2013.04.001

Please cite this article in press as: Nishizaki T, et al., DL-/PO-phosphatidylcholine may shed light on the treatment of Alzheimer dementia,
Personalized Medicine Universe (2013), http://dx.doi.org/10.1016/j.pmu.2013.04.001

2T. Nishizaki et al. / Personalized Medicine Universe xxx (2013) 1e4Fig. 1. Metabolic pathways for phosphatidylcholine and the role of phosphatidylcholine and metabolites in cognitive functions. FFA, free fatty acid.

synaptic transmission [3e6], while lysophosphatidylcholine andlysophosphatidic acid enhances the activity of nACh receptors [7,8]and choline serves as an a7 nACh receptor agonist [9].
a7 nACh receptor is preferentially localized on presynaptic terminals in the brain, where the receptor stimulates the release ofneurotransmitters, including glutamate, and participates in theexpression of long-term potentiation (LTP), a cellular model oflearning and memory [10e16]. Accordingly, cis-unsaturated freefatty acids, lysophosphatidylcholine and lysophosphatidic acidcould induce LTP by enhancing the activity of presynaptic a7 nACh
receptor or activating the receptor (Fig. 1). Additionally, arachidonic
acid serves as a retrograde messenger for LTP expression [17].
DL-PC potentiates a7 nACh receptor responses and induces LTPin an a7 nACh receptor-dependent manner [18]. This indicates thatDL-PC could improve learning impairments. In contrast, PO-PC
enhances long-term depression (LTD), another cellular model oflearning and memory, in concert with decreased expression of thea-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
receptor subunit GluR1 on the plasma membrane [19] (Fig. 1). This
indicates that PO-PC could improve memory disorders byenhancing LTD.

(50 mg/day) and PO-PC (45 mg/day), the effect being still evident
in some subjects 5 years after taking DL- and/or PO-PC (Fig. 2). This
indicates that DL- and/or PO-PC has the potential to ameliorate
cognitive disorders. Notably, taking both DL- and PO-PC (DL/PO-PC)
had a more beneﬁcial effect on cognitive impairment than taking
either DL- or PO-PC alone [20] (Fig. 3).
4. DL/PO-PC is more effective than donepezil at treatingAlzheimer dementia
Here, we introduce data supporting the beneﬁts of DL/PO-PC.
Twenty patients (11 males and 9 females) aged 59e87 years(average, 77  2 years) with Alzheimer disease had taken donepezilhydrochloride (3 mg/day) for more than 1 year, and the MMSE
score at the ﬁrst test ranged from 0 to 18 (Fig. 4A). Donepezil
medication for those patients was stopped, and instead, patients
took a combination of DL-PC (50 mg/day) and PO-PC (45 mg/day).

3. Anti-dementia action of DL- and/or PO-PC in humans
There is evidence to support the anti-dementia effect of DLand/or PO-PC in humans [19,20]. While evaluating the MMSE score(maximum score, 30), a score of less than 20 corresponds to mild
cognitive impairment and dementia. The MMSE test was carriedout on 310 patients (135 males and 175 females) with cognitive
decline and dementia aged 59e95 years (average, 76  1 years). The
initial MMSE score was 17.4  0.3 (Fig. 2), and the score increased toover 20, corresponding to normal cognitive functions, 1 month after
oral intake of DL-PC (100 mg/day), PO-PC (90 mg/day), or DL-PC

Fig. 2. Effect of DL- and/or PO-PC on cognitive disorders in humans. MMSE test wascarried out before and after oral intake of DL-PC (100 mg/day), PO-PC (90 mg/day), orDL-PC (50 mg/day) and PO-PC (45 mg/day). In the graph, each point represents themean (SEM) MMSE score at the periods as indicated (n ¼ 310).

Please cite this article in press as: Nishizaki T, et al., DL-/PO-phosphatidylcholine may shed light on the treatment of Alzheimer dementia,
Personalized Medicine Universe (2013), http://dx.doi.org/10.1016/j.pmu.2013.04.001

T. Nishizaki et al. / Personalized Medicine Universe xxx (2013) 1e43Fig. 3. Beneﬁcial effect of DL-PC plus PO-PC (DL/PO-PC) on cognitive disorders inhumans. MMSE test was carried out once a month before and after oral intake of DLPC, PO-PC, or DL/PO-PC once daily after breakfast. (A) Each point represents the mean(SEM) MMSE score at the periods as indicated for 75 subjects taking DL-PC (50 mg/day) and PO-PC (45 mg/day). ***P < 0.001 as compared with the score before DL/PO-PC(paired t-test). (B) An increase in MMSE score was calculated 5 months after taking DLPC (100 mg/day) alone (21 subjects), PO-PC (90 mg/day) alone (214 subjects), and DLPC (50 mg/day) plus PO-PC (45 mg/day) (75 subjects). Each column represents themean (SEM) MMSE score increase. P values, Dunnett’s test.

Oral intake of DL/PO-PC signiﬁcantly raised the MMSE score from
11.8  1.1 to 19.9  1.6 one year after beginning the treatment(Fig. 4B), but a smaller effect was observed for patients with an
initial MMSE score below 10 (Fig. 4A). This implies that DL-/PO-PC
has a more beneﬁcial effect than donepezil in patients with Alzheimer dementia.
Finally, we present two very impressive cases. The ﬁrst case wasof an 86-year-old woman who had no history of donepezil medication. Initially, she could not draw a clock correctly and her MMSE
score was 10. Surprisingly, after only 1 month of taking DL-PC(50 mg/day) and PO-PC (45 mg/day) she showed drastic

Fig. 5. Example drawings of a clock from two patients who exhibited a drastic
improvement after taking a combination of DL-PC (50 mg/day) and PO-PC (45 mg/day)orally.

improvement; she was able to draw a clock correctly, and herMMSE score increased to 17 (Fig. 5A). The second case was of a 71year-old man who also had no history of donepezil medication. In
the initial test, he arranged the numbers of a clock counterclockwise and scored a 17 on the MMSE. Again, after 1 month of taking
DL-PC (50 mg/day) and PO-PC (45 mg/day) orally, he could draw aclock correctly, and scored 17 on the MMSE (Fig. 5B). These cases
further support the notion that DL-/PO-PC is useful for the treatment of Alzheimer disease.
5. Conclusion
There is deﬁnite evidence that DL-/PO-PC is capable ofimproving dementia including Alzheimer dementia. Accordingly,
DL-/PO-PC could be a promising therapeutic agent for Alzheimer
dementia.
References

Fig. 4. DL-/PO-PC is more effective than donepezil in treating Alzheimer dementia.
Donepezil medication for Alzheimer patients was stopped, and instead, patients took acombination of DL-PC (50 mg/day) and PO-PC (45 mg/day). (A) In the graph, each point
represents the mean (SEM) MMSE score at the periods as indicated (n ¼ 20). (B) In
the graph, each column represents the mean (SEM) MMSE score before (Donepezil)
and 12 months after taking DL-PC (50 mg/day) and PO-PC (45 mg/day) orally (n ¼ 20).
P value, unpaired t-test.

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Please cite this article in press as: Nishizaki T, et al., DL-/PO-phosphatidylcholine may shed light on the treatment of Alzheimer dementia,
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