November 2022

Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

Review

Lysophosphatidic acids in cerebrospinal ﬂuids:
Potential biomarkers and therapeutic targets for neuropathic pain
1

1

2

3

Baasanjav Uranbileg , Makoto Kurano *, Masahiko Sumitani , Nobuko Ito ,4

41

Kuniyuki Kano , Junken Aoki , Yutaka Yatomi
1

Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo,
7‒3‒1 Hongo, Bunkyo-ku, Tokyo 113‒8655, Japan2
Department of Pain and Palliative Medicine, The University of Tokyo Hospital,
7‒3‒1 Hongo, Bunkyo-ku, Tokyo 113‒8655, Japan3
Department of Anesthesiology and Pain Relief Center, The University of Tokyo Hospital,
7‒3‒1 Hongo, Bunkyo-ku, Tokyo 113‒8655, Japan
4
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7‒3‒1 Hongo, Bunkyo-ku, Tokyo 113‒0033, Japan
Abstract Recent advances in lipidomics have allowed for the measurement of precise levels of biologically active lipids
in clinical human samples, which can aid us in understanding the involvement of bioactive lipids in the pathogenesis of human diseases. Among the various human diseases, a variety of membrane lipid-derived mediators have been demonstrated
to possess important roles in the initiation, maintenance, and modulation of neuropathic pain (NP). Lysophosphatidic acid
(LPA) has been identiﬁed as being the main initiator of NP based on experimental animal models, as well as clinical studies
using a lipidomics approach. Currently, there is no speciﬁc medical treatment and no objective laboratory testing for NP.
Based on these conditions, we have described the possible implementation of inhibitors of autotaxin, a producing enzyme
for LPA, and LPA measurements in the cerebrospinal ﬂuid (CSF) as a therapeutic target and a potential diagnostic marker.
Key words: NP: neuropathic pain, CSF: cerebrospinal ﬂuid, LPC: lysophosphatidylcholine, LPA: lysophosphatidic acid, ATX:
autotaxin

Introductionof these lipid mediators in human samples. In addition, theMany elegant basic studies have identiﬁed the important
physiological roles of functional lipids, such as eicosa-

measurement of lipid mediators can sometimes help

1‒8)

noids, lysophospholipids (LPLs), and ceramides

researchers in understanding their unexpected roles in the. To

pathogenesis of human diseases.

introduce the ﬁndings of these basic studies into clinicalIn these translational research and reverse translational

medicine, it is very important to investigate the modulation

research studies, the lipidomics approach via the use ofmass spectrometry functions well. Mass spectrome-* Corresponding author

try-based lipidomics approaches can enable researchers to

Makoto Kurano

detect and quantify many types of lipids; in the past decade,Department of Clinical Laboratory Medicine, Graduate
School of Medicine, The University of Tokyo, 7‒3‒1 Hongo,

research studies in lipidomics have tremendously increased

Bunkyo-ku, Tokyo 113‒8655, Japan
Tel: ＋81‒3‒3815‒5411

due to improved instrumentation, such as the shift from low

Received: May 30, 2022. Accepted: July 25, 2022.
Epub August 29, 2022.

trometry, which separates lipid species from the same lipid
by their cumulative carbon number-double bond index or

DOI: 10.24508/mms.2022.11.002

the composition of their fatty acyl chains . Additionally,

resolution to high mass resolution procedures. In this study,
we used reversed-phase liquid chromatography‒mass spec-

E-mail: kurano-tky@umin.ac.jp

9)85November 2022

Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

we used imaging lipidomics, among other high mass reso-

ATX activity in human melanoma cells was initially22)
reported to be a cell motility stimulating factor . Cur-lution instrumental approaches, such as shotgun lipidomics
and matrix-assisted laser desorption ionization-time of light.

rently, it is now clear that the activity of ATX is a result of

When we previously investigated the modulation of
LPLs in plasma samples taken from subjects with acute cor-

LPA signaling. Therefore, the quantitative determination of

onary syndrome, we ﬁrst observed the possible signiﬁcanceLPA due to the stringent conditions required for the preciseof lysophosphatidic acid (LPA) with a w3 acyl chain andother LPLs, such as lysophosphatidylserine (LPS) and lyso-

measurement of LPA in plasma samples . Serum ATX has

phosphatidylinositol (LPI), in the pathogenesis of acute cor-ﬁbrosis

ATX in serum samples is used as a surrogate marker of23)

been established as a novel and reliable marker of liver

10,11)

24,25). In addition, almost all of the actions of LPA. This observation prompted us toare mediated by its receptors (LPA1‒6), and all of the LPA

investigate their roles in pathological conditions, such as

receptors are expressed in the nervous system and involved
26)
in neurodevelopmental processes , as well as in the initia-

onary syndrome

inﬂammation and platelet activation, which are involved in
12‒15)

the pathogenesis of acute coronary syndrome.

tion of NP.

In this review, we explain the roles of LPA in the pathogenesis of neuropathic pain (NP), which have been pro-2.

posed from basic studies and clinical research that has pri-

LPA in Neuropathic Pain
NP is a chronic pain with refractive characteristics, and it

marily been conducted by our team via a lipidomics

occurs due to damage to the somatosensory neuronal axes.

approach; additionally, we discuss possible future medical

The clinical phenotypes of NP are quite diﬀerent fromthose of acute pain, which is eﬀectively treated with non-applications.

1.

steroidal anti-inﬂammatory drugs (NSAIDs) and opioids in

LPA-LPC-ATX Axis

a consistent manner, even though the initial cause of thepain has been resolved. NP exhibits abnormal pain symp-

Lysophosphatidic acid (LPA) is one of the biologically
active lipid mediators that acts through its deﬁned G pro-toms, such as hyperalgesia and allodynia, and it is divided

tein-coupled receptors LPA1‒6 and is mainly produced byinto two broad categories known as peripheral and central

autotaxin (ATX) from lysophosphatidylcholine (LPC)
extracellularly, and from phosphatidic acid (PA) via diacy-

NP, depending on the location of the damage. Additionally,
it occurs as a secondary symptom in lumbar spinal canal5)

lation of phospholipase A2 (PLA2) intracellularly . LPA is
involved in many cellular and biological processes, includ-

stenosis (LSS), diabetes, herpes zoster infections, the27)

eﬀects of chemotherapy, and after a stroke .

ing cell proliferation, migration, anti-apoptotic actions, theMultiple mechanisms, as well as the key molecules inenhancement of secretion of cytokines and chemokines, thethese mechanisms, including cytokines (Il-6, TNFa), chemokines, brain-derived neurotrophic factor (BDNF), neu-

16)

17)

induction of arteriosclerosis , cancer cell invasion , and18)

neuropathic pain (NP) .

rotransmitters (GABA and glutamate), neurotrophins (nerve
growth factor), VGF-derived neuropeptides, ATP, lipid

In the last two decades, many studies have been performed by diﬀerent groups on the physiological and patho-

mediators (prostanoids and lysophospholipids), and theirlogical roles of LPA and its related factors, including LPC,

receptors, have been demonstrated to be involved in the

ATX, and LPA receptors. Although the receptors have not

manifestation of NP symptoms

28‒30).

A variety of biologically active lipids are produced

been identiﬁed, LPC is also a biologically active lipid
19)
known to act as a pro-inﬂammatory , oxidative stress, andduring NP, wherein some of the lipids are induced, whereas
others prevent its progression. Among these proposed mole-

20)

apoptosis inducing factor , in addition to being a substrateof ATX for the production of LPA. LPC is produced fromcules, LPA is promising for NP initiation and maintenance.
In 2004, Ueda et al. ﬁrst demonstrated that the LPC-LPA-

phosphatidylcholine (PC) which is the major component of
the cell membrane, via the cleavage of PLA2. Moreover,
ATX is one of the well-studied enzymes associated with

LPA1 axis is involved in the pathogenesis of pain via basic

LPA signaling and exhibits widespread tissue expression

production or conversion from LPC extracellularly via thewith high levels in the brain, which results in higher levels

action of ATX. LPC itself was also reported to be directly

21)

involved in NP, mainly explained by its conversion toexperiments. A source of LPA can be explained by its local

of it in the cerebrospinal ﬂuid (CSF) than in the blood .
86November 2022

Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

mulation of microglia

38,39).

Concordant with previous reports

31‒36), we have also

demonstrated increased levels of LPA and LPC in both thespinal cord or dorsal root ganglion (DRG) tissue samples
and in the CSF, wherein we used lipidomics approaches in
two diﬀerent animal models for NP. One model involved apreclinical model of the narrowing of the spinal canal or
cauda equina compression (CEC) without the direct injury
of the nerve, while still resulting in NP with motor dysfunc40)

tion . The other is LSS model or mechanical compressionof the dorsal root ganglion (CD) with a decreased threshold41)

of pain . In both studies, LPC and LPA measurements
were performed in the plasma, CSF (Fig. 1), and spinal cord
or DRG tissue samples, in conjunction with the characterization of the behavior. The chromatograms of various LPC
and LPA species in CSF shown in Fig. 2. In the CEC model
study, we conﬁrmed the involvement of LPA in NP initiation and maintenance by measuring LPC, LPA, and theexpression levels of LPA receptors in a time-course manner,and the increased levels of LPC species were also con40)
ﬁrmed via the MALDI-MSI analysis . The levels of LPA
Hypothetical scheme of the involvement of lysophosphatidic acid and its receptors 1 and 3 in themechanism of neuropathic pain.

Fig. 1.

and LPC that were measured in the CSF of patients with42)

NP demonstrated associations with the degree of pain

and

43)

the severity of symptoms . All of these animal models andclinical studies demonstrated crucial roles of the LPA-LPC-

In two diﬀerent NP models, under the compression of
the spinal cord or DRG, LPC, which is a substrate of
ATX, increases in the CSF. The level and activity of
the ATX enzyme that produces LPA from LPC are notchanged. LPA levels were also increased in CSF andacted on neurons, microglia, and astrocytes through its
receptors LPA1 and LPA3, which play important roles in
the feed-forward system underlying NP.

ATX axis in NP, among other factors involved in the pain
mechanism (Fig. 1).

3.

CSF Is an Ideal Sample to Measure LPA
To introduce the physiological roles of LPA that havebeen demonstrated by basic studies into clinical settings,
18)

LPA . The direct plantar administration of LPA initiatednociceptive responses that were abolished by a genetic deﬁ-

we and other researchers have measured LPA levels byusing liquid chromatography-tandem mass spectrometry

ciency of LPA1 or pretreatment with the LPA1 expression
31)
inhibitor Rho-kinase , and the intrathecal application of(LC‒MS/MS) in the blood , CSF , synovial ﬂuid , asci-

LPA resulted in NP behaviors in animal experiments. Many
studies have suggested that there are direct and indirect

amounts of both substrate (LPC) and enzyme (ATX), thus
resulting in the synthesis of LPA even after sample collec-

involvements of LPA and LPA1 in demyelination, allodynia,
demyelination-associated sprouting, and abnormal pain syn-tion, which requires stringent conditions by suppressing the49)
activity of platelets or by inhibiting ATX . In healthy peo-

apses by using NP model animals and procedures including
peripheral sciatic nerve ligation (pSNL) and ex vivo prepa-

ple, CSF has larger quantities of ATX than in blood sam-rations. The stimulation of LPA1 was shown to lead tothe upregulation of Cav α 2 δ 1, which enhances pain trans-

LPC . Considering the low endogenous concentration of

mission and becomes a reason for hyperalgesia . Whenand less
environmental inﬂuences by blood cells on lipid concentra-

44)

47)

45)

46)

48)

tes , and aqueous humor . Blood samples contain highples, whereas CSF has almost no measurable levels of

32‒36)

45)

50)

the lipids around 500 times lower than in serum

37)

regarding other LPA receptors, LPA3 was reported toamplify LPA production through the activation and accu-

tions

51, 52), we believe that CSF is one of the most suitablespecimens among above mentioned biological ﬂuids,
87

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Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

Fig. 2.

Chromatograms for LPC and LPA species in CSF samples.

The representative chromatograms of various molecular species of the LPC and LPA in CSF samples are shown.

88

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Fig. 3.

Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

Inﬂuence of incubation time and temperature on
the concentration of the LPA in the serum or CSF
samples.

Fig. 4.

LPC and LPA levels were higher in the patientsʼ
CSF with severe NPSI group.
LPC and LPA species were higher in severe than mild
NP patient CSF samples as classiﬁed by the Japaneseversion of the neuropathic pain symptom inventory(NPSI) and Zurich Claudication Questionnaire (ZCQ)
scores.

Incubation time and temperature-dependent changes
were subtle in the CSF. LPA levels were not altered incomparison to the plasma/serum LPA levels.

including blood samples, for the evaluation of lysophospholipids (LPLs), such as LPA. We evaluated the matrix eﬀects
together with validation of the within-run and between-day

NP symptoms with LPA.

precisions by using CSF with low or high LPLs levels andAs mentioned in the Introduction, lumbar spinal stenosis

45)

a standard mixture . In CSF samples, we observed much

(LSS) is one of the diseases representing NP in elderly

smaller changes in LPL levels dependent on incubation

patients, with the following pain symptoms being observed:

time at room temperature than in serum samples, as shownin Fig. 3, which suggested usefulness of the LPLs measure-

low back pain, radiating lower leg pain (with or withoutments in CSF in clinical laboratory settings. Invasiveness inof 28 patients with LSS and 15 control patients were

sampling CSF, compared with other samples, was the only
disadvantage of using LC-MS/MS, however the merit

enrolled in our study , and CSF was also used as the mainfoot numbness), and dysesthesia. For further study, a total
43)

should overcome this invasiveness, in the situation where itmeasurement tool for this study for the measurement of
LPLs. In addition to NPSI, the Zurich Claudication Ques-

is diﬃcult to judge the suitability for operation.

tionnaire (ZCQ) was completed by all of the participants.

4.

Based on these scoring systems, LSS patients were grouped

LPA in CSF in Human Neuropathic Pain

into mild and severe groups. All of the measured LPLs,

There have been two clinical studies conducted by our

including LPC, LPA, and lysophosphatidylinositol (LPI),

group wherein we used CSF obtained from NP patientswere signiﬁcantly higher in the CSF of LSS patients than inwith diﬀerent etiologies for the measurements of the LPC

the control group . In addition to these ﬁndings, the levels

42,43)

43). Basedof some species of LPC and LPA were signiﬁcantly higher

on accurate selection, the participating patients pain symp-

in the severe group than in the mild group of LSS patients.

toms were assessed by using the Japanese version of the

Total LPA or all of the molecular species of LPA were

neuropathic pain symptom inventory (NPSI) and theshown to be strongly correlated in severe group patients

numeric rating scale (NRS) for further assessment. A total

with total LPC or corresponding species of LPC, accordingof 12 molecular species of LPC and LPA were measured by42)
using LC-MS/MS in 18 patients . Total LPA was signiﬁ-

to the NPSI scoring . These clinical studies indicated an
association of LPA levels that were measured in the CSF

cantly correlated with total NPSI (including pressing painwith NP symptoms and disease severity.

and LPA to investigate their association with NP

43)and paroxysmal pain) scores and average NRS scores (Fig.

In addition, NP induced an eﬀect of chemotherapy, especially

4). Total NPSI scores were correlated with 18:1 and 20:4

with taxane, which was associated with genetic polymorphisms

LPA, whereas average NRS scores correlated with 16:0,(two single nucleotide polymorphisms) of LPA1 but not with

16:1, and 18:1 LPA. All of the molecular species of LPA
were clearly and positively correlated with the correspond-

LPA2‒6 . The screening of the genetic polymorphisms in LPA1
could predict the possible onset of chemotherapy-induced NP,

53)

42)

ing LPC species . This study indicated an association ofwhich will be associated with eﬀective therapy.
89

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Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

LPC, was not changed during the study, except for its activity, which was totally inhibited in the plasma and partiallyinhibited in the CSF

40,41)

when the ATX inhibitor was orally

administered (Figs. 1, 5). These studies demonstrated theimportance of the LPA-LPC-ATX axis in NP and suggested
the possible use of the ATX inhibitor for the treatment of
NP (at least the type of NP caused by LSS).

6.

Perspective for the Clinical Usefulness of
Lipidomics for Neuropathic Pain
Our clinical and basic research with lipidomics methods, as

described above, conﬁrmed the involvement of LPA in
human NP. These results have demonstrated the possible
medical application of these ﬁndings as biomarkers and theraFig. 5.

peutic targets. When regarding applications for clinical labo-

Increased LPC and LPA levels were decreased
due to inhibition of ATX with amelioration of pain
symptoms.

ratory testing, the measurements of LPA and/or LPC in the
CSF can be an objective marker for quantifying the degree ofpain or for the diagnosis of the underlying diseases causing

Schematic model
model ofofthe
theeﬀect
eﬀectof of
ATX
ATX
activity
activityin thein CD
theCD model.
model.
When
When
ATXATXis fully
is fully
active,active,the levels
the levelsof LPCof LPC(yel(faintsymbol)
lowsymbol)and
and
LPA
LPA
(red(dark
symbol)symbol)increaseincreasein theinCSF.
theCSF.ATXThe
The inhibitor
ATX inhibitor
suppressed
suppressed
ATX activity
ATX activity
and predict
andpredictededbeyondbeyond
the production
the productionof LPA.ofThe
LPA.
threshold
The thresholdof theof thewas
pain
pain
recoveredwas recoveredfrom mechanicalfrom mechanicalpain by pain
administraby administration
tion
of an ATX
of an
inhibitor
ATX inhibitor(green arrow).
(dark straight arrow).

5.

pain. At present, no quantitative clinical laboratory testing
exists for the evaluation of pain, and physicians evaluate thedegree of pain by using complicated and subjective questionnaire forms. Moreover, the elevation of LPA and/or LPC will
exclude patients with pain in which psychogenic factors arelargely involved. Our recent study suggested that the mea-

The LPA-LPC-ATX Axis Is a Potential
Therapeutic Target for Neuropathic Painsurements of LPA and/or LPC will also be useful to discrimi-

The involvement of LPA in human pain diseases, asnate the neuropathic pain caused by LSS from that caused by
non-LSS diseases, such as diabetic neuropathy. Therefore, thedescribed above, prompted us to investigate the possibility

development of LPA and LPC measurement systems in CSF

that LPA is a target for the treatment of NP. As mentioned

will help physicians in evaluating the degree of pain and inabove, LPA is produced from LPC by ATX activity andjudging the application of surgical treatment.

induces NP via its LPA1,3 receptors (Fig. 1). In the CDmodel, an aligned study using an ATX inhibitor (ONO-

Similar to our study in the area of NP, as reviewed in thepresent article, the lipidomics approach will largely contrib-

8430506) was performed to prove the possibility of the
LPA-LPC-ATX axis as a potential therapeutic target in NP

ute to the understanding of human diseases and can facili-(Figs. 1, 5). Obviously, in the CSF, the levels of LPC andin various diseases.

tate translational and reverse translational research studiesst

LPA were increased from the 1 day after surgery with atime course-dependent decrease in CEC but were sustained

Acknowledgments
This work was supported by:at high levels in the CD model (Figs. 1, 5). These increased
levels of LPA returned to levels similar to those of the con-

AMED Advanced Projects for Medical Innovation (LEAP)

trol when the ATX inhibitor was orally administered (Fig.

(JA, YY)

5). The therapeutic eﬀects were also observed in the

AMEDmechanical threshold of the pain, which was signiﬁcantly(19lm0203084h0001) (YY, MK, MS, JA)
JSPS a Grant-in-Aid for Scientiﬁc Research on Innovative

decreased on the ipsilateral side, as shown in Fig. 5. The

Translational

involvement of microglia and astrocytes was also inhibited41)
in a time-dependent manner . The expression level ofAreas 15H05906 (YY)

ATX, which is a limiting enzyme for producing LPA from

20H03573 (MK)Research

Network

Program

JSPS KAKENHI grant numbers 16H06236 (MK) and90

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Medical Mass Spectrometry Lipidomics Vol. 6 No. 2

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