Hindawi Publishing Corporation

PPAR Research
Volume 2014, Article ID 768594, 9 pages
http://dx.doi.org/10.1155/2014/768594

Review Article
Role of PPAR𝛾 in the Differentiation and Function of Neurons

Rodrigo A. Quintanilla,1,2 Elias Utreras,3 and Fabián A. Cabezas-Opazo1

1
Centro de Investigación Biomédica, Universidad Autónoma de Chile, Carlos Antúnez 1920, 750056 Santiago, Chile
2
Laboratorio de Neurociencias, Departamento de Neurologı́a, Escuela de Medicina,
Pontificia Universidad Católica de Chile, 8330024 Santiago, Chile
3
Laboratorio de Dinámica Celular y Neuronal, Departamento de Biologı́a, Facultad de Ciencias,
Universidad de Chile, Ñuñoa, 7800003 Santiago, Chile

Correspondence should be addressed to Rodrigo A. Quintanilla; [email protected]

Received 22 May 2014; Revised 31 July 2014; Accepted 16 August 2014; Published 26 August 2014

Academic Editor: Paul D. Drew

Copyright © 2014 Rodrigo A. Quintanilla et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.

Neuronal processes (neurites and axons) have an important role in brain cells communication and, generally, they are damaged in
neurodegenerative diseases. Recent evidence has showed that the activation of PPAR𝛾 pathway promoted neuronal differentiation
and axon polarity. In addition, activation of PPAR𝛾 using thiazolidinediones (TZDs) prevented neurodegeneration by reducing
neuronal death, improving mitochondrial function, and decreasing neuroinflammation in neuropathic pain. In this review, we will
discuss important evidence that supports a possible role of PPAR𝛾 in neuronal development, improvement of neuronal health,
and pain signaling. Therefore, activation of PPAR𝛾 is a potential target with therapeutic applications against neurodegenerative
disorders, brain injury, and pain regulation.

1. Introduction and retinoic acid receptor (RXR), and then this complex will
bind to specific PPRE regions in the DNA to activate different
1.1. Peroxisome Proliferator Activated Receptors. Peroxisome target genes [4]. In addition, this dimer can interact with
proliferator activated receptors (PPARs) are nuclear receptors other coactivators proteins like CBP/p300, SRC1, PBP, and
that induce signaling and transcription of different pathways PGC-1𝛼 to induce a specific gene expression (Figure 1) [3, 4].
[1]. Generally, they participate in the regulation of lipids PPAR𝛼 expression is abundant in liver, kidney, and heart
metabolism and glucose homeostasis, and they also are acti- and commonly is present in tissues with high metabolic rate
vated by specific ligands [1–3]. The family of PPARs is mostly [1, 4]. PPAR𝛼 is activated by polyunsaturated fatty acids,
composed of three known isoforms: PPAR𝛼, PPAR𝛽/𝛿, and like docosahexaenoic acid (DHA) and icosapentaenoic acid
PPAR𝛾. These receptors share a structural homology that (EPA), and by fibrate drugs like gemfibrozil and fenofibrate,
consists of four functional units (A, B, C, and D) [1–3]. Unit which are currently used as a treatment for dyslipidemia,
A/B, located in N-terminal region of the receptor, controls metabolic syndrome, and cardiovascular damage [1, 3, 4].
the activation domain by AF-1 ligand, and Units C and D PPAR𝛽 expression is ubiquitous and their abundance
present a DNA binding domain that includes two zinc fingers depends on the tissue [5]. To this date, evidence suggests that
motives and a docking domain [1–3]. The C-terminal region PPAR𝛽 is activated like PPAR𝛼 and apparently plays a role in
contains a specific binding domain and a transactivation embryo development [5].
domain for AF-2 [2]. This region is very important for PPAR𝛾 is expressed principally in fatty and vascular tissue
nuclear localization of the PPARs and other interactions with [6, 7]; however, it has showed their presence in heart and
activator proteins [1–3]. brain tissue, where their activation reduced cardiovascular
The binding of specific agonists activates the PPARs damage and neurodegeneration [6, 7]. PPAR𝛾 is activated
response, forming a heterodimer complex between PPARs by natural ligands like linoleic acid (9- and 13-HODE) and
2 PPAR Research

PPARs ligands

PPARS Retinoic
RXR acid

CBP/p300
SRC1
PBP
Nucleus PGC1-𝛼

Cofactor Transcriptional response

- Metabolism
RXR - Inflammatory response
PPARS
- Adipogenesis
DNA - Mitochondrial proteins

Figure 1: Overview of PPARs signaling and activation. The figure shows how PPARs are activated. PPARs ligand enters the cell where it binds
to promote receptor dimerization with receptor of 9-cis-retinoic acid (RXR). This complex migrates to the nucleus where it binds to DNA
and to different cofactors proteins (CBP/p300, SRC1, PBP, and PGC1-𝛼), to induce the expression of several genes involved in metabolism,
inflammatory response, and antioxidant defense.

by prostaglandin derivative, 15-deoxi-Δ12,14 -prostaglandin J2 that treatment with PPAR𝛾 activators delayed neurodegen-
(15d-PGJ2 ), which regulates inflammatory response [3]. Clin- eration [10]. PPAR𝛾 agonists have also showed benefits in
ical importance of PPAR𝛾 has risen especially after the use of experimental models of stroke and ischemia [11–13]. In gen-
TZDs drugs for the treatment of diabetes mellitus type 2 [8, eral, activation of these receptors reduced inflammation and
9]. Treatment with TZDs activates PPAR𝛾 pathway reducing apoptosis and improved memory function [11–14]. Moreover,
insulin resistance and blood glucose levels in patients with in a mice model of amyotrophic lateral sclerosis (ALS), a
diabetes type 2 [9]. disease that causes paralysis due to loss of motor neurons,
Interestingly, the activation of PPAR𝛾 receptors by TZDs treatment with PPAR𝛾 agonists like rosiglitazone extends
prevented neurodegeneration and promoted neuronal devel- survival and decreases motor neuron loss [15–17].
opment in primary neuronal cultures [10]. Beneficial effects of PPAR𝛾 activators also have been
studied in mice models of Alzheimer’s disease (AD). AD
2. PPAR𝛾 Activation Prevents is a neurodegenerative disorder that affects a large segment
Neurodegeneration of older population and clinically is characterized by a
progressive memory decline of the patient and, later, the
In this review, we will discuss evidence that suggests an presence of brain aggregates of a protein called amyloid-
important role of PPAR𝛾 in brain function, neuronal develop- 𝛽 (A𝛽) and the accumulation of the hyperphosphorylated
ment, and pain signaling. For the studies that cover neuropro- form of the tau protein, which later forms intraneuronal
tective effects of PPAR𝛾, we will discuss evidence produced aggregates known as neurofibrillary tangles (NFTs) [18].
in different study models (animal, cells, and patients), which Some studies explored the possibility that PPAR𝛾 activation
supports the use of PPAR𝛾 activation against neurodegener- reduced neuropathological changes in different AD mice
ation. For the effects of PPAR𝛾 promoting neuronal devel- models. For instance, PPAR𝛾 activation by some TZDs
opment, we will describe evidence obtained from neuronal drugs reduced amyloid deposition and reversed cognitive and
stem cells (NSCs) and primary neuronal cultures. Finally, as memory decline in some AD transgenic mice models [18–
an extension of this review, we will discuss other neurological 21]. Treatment with PPAR𝛾 agonist rosiglitazone improved
pathways where PPAR𝛾 could be an important player. hippocampus cognition in the Tg2576 AD mice with no effect
on wild type mice [21]. Tg2576 transgenic mouse is an AD
2.1. Animal Studies. Agonists of PPAR𝛾 have been used study model that presents amyloidosis (accumulation of A𝛽),
to reduce neurodegenerative changes in mice models that neuronal loss, and cognitive decline [21]. In a different study,
mimic several neurodegenerative diseases [10]. For example, oral treatment with PPAR𝛾 agonist pioglitazone reduced
studies performed in a transgenic mouse that resembles the A𝛽 levels within the cortex in the APPswe/PSEN1𝛿E9
experimental autoimmune encephalomyelitis (EAE) showed (APP/PS1) mice, another mouse model that accumulates A𝛽
PPAR Research 3

plaques similar to neuropathological features presented in a mouse that overexpresses human PGC-1𝛼 exacerbated
AD [22]. In addition, chronic pioglitazone treatment reduced amyloid and tau pathology [27]. AD-like pathology was
expression of inflammatory cytokines and enhanced phago- accompanied by mitochondrial dysfunction, neuronal death,
cytosis of deposited forms of A𝛽 [22]. More importantly, and an exacerbated hyperactivity in the Tg19959/PGC1-𝛼
reduction in amyloid plaque levels was associated with a mice [27].
reduction of cognitive defects in the drug-treated APP/PS1 Beneficial effects of PPAR𝛾 had been investigated in other
mice [22]. Further studies in Tg2576 AD mice extend the neurological conditions. The stroke is a devastating disease
use of PPAR𝛾 activators against neurodegeneration [23]. with limited treatment options. In this context, several groups
Tg2576 mice showed significant impairment in memory and have explored the use of PPAR𝛾 activators against neuronal
cognition compared with wild type mice [23]. Tg2576 AD injury [29]. For example, treatment with PPAR𝛾 agonists
mice treated with rosiglitazone improved neuronal function reduced injury and inflammation in a rat model of transient
indicated by an increase in neuronal activity [23]. These cerebral ischemia [29]. Complementary studies examined
effects were correlated with an increase in the expression of PPAR𝛾 expression, DNA binding, and PPAR𝛾 transcriptional
presynaptic proteins that are reduced in patients with AD activity after stroke induced in rats [30]. PPAR𝛾 expression
[23]. was dramatically increased in ischemic neurons and the
In AD, the inflammatory response is exacerbated in treatment with T0070907, a PPAR𝛾 antagonist, reversed
glia and astrocytes and accumulative evidence indicates rosiglitazone-mediated protection after stroke [29].
that neuroinflammation contributes to neuronal dysfunction Beneficial effects of PPAR𝛾 activators were investigated
[18]. Interestingly, Heneka et al. studied if PPAR𝛾 activation in mice models subjected to damage for ischemia [29–31].
reduces the expression of proinflammatory cytokines, in In response to ischemia, expression of PPAR𝛾 gene was
order to improve neuronal injury observed in AD [18]. Acute significantly increased in neurons, suggesting that neuronal
treatment of 10-month-old APPV717I mice with pioglitazone PPAR𝛾 may be a primary target for PPAR𝛾-agonist-mediated
significantly decreased the number of activated microglia neuroprotection [30, 31]. In other studies, Zhao et al. eval-
and astrocytes in hippocampus and cortex [18]. In addi- uated the contribution of PPAR𝛾 to ischemic injury, gen-
tion, pioglitazone treatment reduced the expression of the erating conditional neuron-specific PPAR𝛾 knock-out mice
proinflammatory enzymes like cyclooxygenase 2 (COX2) and (PPAR𝛾-KO) [32]. PPAR𝛾 deficiency caused increased brain
inducible nitric oxide synthase (iNOS). Finally, pioglitazone damage and oxidative stress in response to cerebral artery
treatment reduced amyloid deposits in the hippocampus and occlusion [32]. Primary cortical neurons from PPAR𝛾-KO
cortex [18]. Complementary studies by Yamanaka et al., using mice showed increased neuronal death, reduced expression
the PPAR𝛾 agonist pioglitazone and a novel selective PPAR𝛾 of SOD1 (superoxide dismutase 1), catalase, glutathione S-
modulator, DSP-8658, observed an increase in microglial transferase, and uncoupling protein-1 (UCP-1) after ischemia
activation and phagocytosis in the APPV717I mice [24]. [32], suggesting that PPAR𝛾 is an important factor in the
PPAR𝛾 activators increased A𝛽 phagocytosis through the regulation of the antioxidant response in the brain.
upregulation of scavenger receptor CD36 [24]. Further- PPAR𝛾 effects were also investigated in animals submitted
more, DSP-8658-treated mice showed improvement in spatial to spinal cord injury (SCI) [33]. Compared with the control
memory performance in APPV717I mice [24]. groups, rosiglitazone treatment significantly increased loco-
Further studies explored the role of PPAR𝛾 on cyclin- motor recovery, reduced NF-𝜅B expression, and increased
dependent kinase 5 (Cdk5) pathway. Cdk5 is a kinase that the proliferation of endogenous neuronal precursors cells
apparently plays an important role in neurogenesis and (NPCs) in animals subjected to spinal injury [33].
its deregulation is involved in the pathogenesis of AD Finally, the protective role of a natural PPAR𝛾 ligand and
[25]. Interestingly, effects of early lethality, astrogliosis, and 15-deoxy-delta12,14-prostaglandin J2 (15-PGJ2 ) in ischemia-
increased neuroinflammation were observed in Cdk5 condi- reperfusion has been reported [34]. The treatment with 15d-
tional knock-out mice [25]. More importantly, these effects PGJ2 decreased expression of autophagic proteins (LC3-
were significantly reduced with the pioglitazone treatment II, Beclin 1, cathepsin-B, and LAMP1) in ischemic cortex
[26]. of animals with artery occlusion, exerting neuroprotection
Despite large evidence discussed above where PPAR𝛾 through the inhibition of neuronal autophagy [34].
activation ameliorates neurodegenerative effects in AD and
other neurological diseases, some studies had showed oppo- 2.2. Neuronal Cells Studies. As we described before, PPAR𝛾
site results. For example, a recent study published by Dumont has been proposed as a therapeutic target against neu-
et al. explored the effects of peroxisome proliferator-activated rodegenerative diseases because of its anti-inflammatory
receptor coactivator-𝛼 (PGC-1𝛼) expression in the Tg19959 action in glial cells [18, 22]. However, several reports indi-
mice, another AD mice model that has increased A𝛽 levels cate that PPAR𝛾 agonists induce neuroprotective actions
and memory deficits [27]. Binding of PGC-1𝛼 with PPAR𝛾 through an independent pathway [35, 36]. For example,
induces the expression of different proteins involved in the Fuenzalida et al. showed that the rosiglitazone protected
regulation of mitochondrial biogenesis [28]. Other studies hippocampal neurons against A𝛽 toxicity and apoptosis
in Huntington disease (HD) showed a significant reduction induced by nerve growth factor (NGF) deprivation [35].
in mRNA PGC-1𝛼 levels, the event that could contribute The protective effects of rosiglitazone were associated with
to the pathogenesis of this disease [28]. Surprisingly, these an increase in the expression of Bcl-2, an antiapoptotic
studies showed that the crossing of the Tg19959 mice with protein [35]. Interestingly, PC12 cells expressing a dominant
4 PPAR Research

negative mutant of PPAR𝛾 showed an enhanced sensitivity and reduced oxidative stress that occurred when striatal cells
to neurotoxic changes induced by A𝛽, including apoptosis, that express mutant huntingtin were challenged with calcium
neurites damage, oxidative stress, and mitochondrial injury stress [43].
[35]. In the same context, our group explored the effects
of PPAR𝛾 activators on hippocampal neurons treated with
2.3. Clinical Studies. Positive results of PPAR𝛾 activators
A𝛽 [36]. These studies showed that activation of PPAR𝛾 by
against neurodegeneration in cell lines and animal models
troglitazone and rosiglitazone protects hippocampal neurons
have encouraged testing these compounds in patients affected
against A𝛽-induced neurodegeneration [36]. In addition,
by neurodegenerative disorders [18–21]. For instance, the
PPAR𝛾 activation results in the modulation of Wnt signaling
effects of the PPAR𝛾 agonist pioglitazone on cognition, cere-
components, including the inhibition of glycogen synthase
bral blood flow (CBF), and plasma levels of A𝛽 were tested in
kinase-3𝛽 (GSK-3𝛽) and an increase of the 𝛽-catenin levels
a controlled trial in patients with mild AD during 6 months
[20, 36]. GSK-3𝛽 is a kinase that has been suggested to
[29]. Patient group treated with pioglitazone improved cogni-
be responsible for the anomalous tau hyperphosphorylation
tion and CBF, while untreated group showed no improvement
in AD [37], and the activation of Wnt pathway by proper
[29]. The plasma A𝛽40/A𝛽42 ratio increased in the control
Wnt ligands protected hippocampal neurons and AD mice
group but showed no significant changes in the pioglitazone
exposed to A𝛽 [38].
group [29]. In another study, authors evaluated the effects of
Also, protective effects of PPARs activators on neuronal
rosiglitazone on cognition and plasma levels of A𝛽 in AD
cells have been related with an increase in the antioxidant
patients [30]. Patients with AD that received rosiglitazone
response [16, 17, 39]. For instance, Santos et al. showed that an
exhibited an improvement in memory (at the 4th and 6th
increase in peroxisomal proliferation attenuated A𝛽 toxicity
months) and selective attention (the 6th month) compared
in hippocampal neurons [39]. Pretreatment with Wy-14.463
to untreated patients [30]. Plasma A𝛽 levels were unchanged
(Wy), a peroxisome proliferator and a PPAR𝛼 activator,
in subjects treated with rosiglitazone but decreased for
prevented neuronal death and neurites loss induced by the A𝛽
untreated subjects [30].
[39]. Moreover, neurons treated with this compound showed
In addition, in a case report, Sundararajan et al. investi-
an increase in the number of peroxisomes, with a concomi-
gated the therapeutic potential of pioglitazone in a patient
tant increase in catalase activity, reducing the production of
with secondary progressive multiple sclerosis (MS) [31].
intracellular reactive oxygen species (ROS), and prevented
Treatment with pioglitazone attenuated her cognitive decline
mitochondrial dysfunction in neurons exposed to both H2 O2
and improved fine coordination, and after 3 years of treat-
and A𝛽 [39].
ment the patient continued being clinically stable, with no
PPAR𝛾 agonists have also been tested in neuronal cells
adverse events [31]. Also, in a randomized controlled trial
treated with acetaldehyde, a toxin that mimics Parkinson
of 5238 patients with diabetes type 2 who had evidence of
disease (PD) neurodegeneration [40]. Acetaldehyde is an
macrovascular disease, treatment with pioglitazone for 34
inhibitor of mitochondrial function and induced oxidative
months reduced the combined risk of heart attacks, strokes,
stress and apoptosis in neuronal cells [41]. In these studies, the
and death by 16% in high-risk patients [32]. In a different
apoptosis induced by acetaldehyde was moderately reversed
study, 30 stroke patients received treatment with pioglitazone
by rosiglitazone treatment in human neuroblastoma SH-
or rosiglitazone for 36 days after accident [33]. Treatment
SY5Y cells [41]. In addition, the treatment with rosiglitazone
with PPAR𝛾 agonists showed a significant improvement in
induced the expression of antioxidant proteins like Bcl-2
functional independence measure (FIMTM), indicating that
and Bax [41]. Complementary studies examined the role of
the administration of TZDs drugs improved their func-
PPAR𝛾 activation against PD in neuronal cells treated with 1-
tional recovery by the modulation of the neuroinflammatory
methyl-4-phenylpyridinium ion (MPP+ ). MPP is an inhibitor
response following stroke [33].
of mitochondrial complex I that has been widely used as
a neurotoxin that mimics PD-like syndrome [42]. Human
neuroblastoma SH-SY5Y cells treated with both MPP+ and 2.4. The Unsuccessful Use of PPAR𝛾 Activators against Neu-
rosiglitazone showed a reduction of apoptosis and an increase rodegeneration. Despite all evidence that suggests PPARs
in the expression of superoxide dismutase (SOD) and catalase activators prevented or delayed neurodegenerative changes,
[42]. several studies delivered conflict results [29, 45–47]. For
Important evidence indicates that PPAR𝛾 activators can instance, in phase III trial studies, memory cognition was not
ameliorate neurodegeneration in HD [28, 43–45]. HD is significantly improved in AD patients treated with PPAR𝛾
a neurodegenerative disease caused by the pathological activators [47]. This evidence suggests that perhaps the
elongation of CAG repeats in exon 1 of the huntingtin mechanism of the action of PPAR𝛾 agonists in animal models
protein gene and is characterized by dysfunction and loss of amyloid deposition may differ from those in humans
of striatal and cortical neurons [44]. Accumulative evidence [48]. Other studies showed no evidence of improvement
suggests that mitochondrial impairment could be part of in cognition and functional tasks, in AD patients treated
neuropathological mechanisms behind HD [28, 44]. In this with rosiglitazone [47, 48], and in AD patients positive for
context, previous findings of our group studied the potential apolipoprotein 𝜀4 allele, the treatment with rosiglitazone
neuroprotective role of PPAR𝛾 activation on preventing the showed a significant decline in cognition [48]. Complemen-
loss of mitochondrial function in HD [43, 44]. PPAR𝛾 acti- tary studies in ALS showed that, in a phase II clinical trial,
vation by rosiglitazone prevented the mitochondrial failure the treatment with pioglitazone had no positive effects on
PPAR Research 5

the survival of ALS patients treated with riluzole (a drug that cells has been demonstrated in different studies [58, 59].
extends lifespan of ALS patients) [49]. PPAR𝛾 is expressed in the central nervous system [30, 36],
In addition, studies using different neuronal cell models and 15d-PGJ2 , a natural PPAR𝛾 ligand, stimulated neurite
showed no benefit of PPAR𝛾 activation against neurode- outgrowth in pheochromocytoma 12 (PC12) cells stimulated
generation [50]. For instance, studies that explored positive with NGF [60]. In addition, we reported that PPAR𝛾 is
effects of troglitazone and pioglitazone against ALS showed present in rat hippocampal neurons and that its activation
that treatment with both drugs did not promote the survival by TZDs prevented axon degeneration, neurite loss, and
of hippocampal neurons and rat motoneurons [50]. Also, it mitochondrial impairment induced by A𝛽 [35, 36]. Impor-
has reported that treatment with 15d-PGJ2 induced neurite tantly, the treatment with troglitazone induced an increase in
degeneration and nuclear fragmentation, in primary neu- axon length and neurite outgrowth compared with untreated
rons and SH-SY5Y neuroblastoma cells [51]. Moreover, the neurons [36, 61].
combined treatment with both ciglitazone (another PPAR𝛾 In addition, the role of PPAR𝛾 in neuronal development
agonist) and 15d-PGJ2 generated neurotoxicity in cultured has been studied in neuronal cells treated with retinoic
cerebellar granule neurons, in a dose response manner [52]. acid (RA) [62]. RA regulates gene expression by activating
Finally, secondary effects of PPAR𝛾 activators have been the nuclear retinoic acid receptor (RXR) inducing neuronal
reported in several neurodegenerative diseases [53]. For outgrowth in neuroblastoma cells [63]. Activation of RA
example, in Friedreich’s ataxia the use of TZDs drugs caused induced differentiation of stem cells to neuronal progenitors
a decrease in the number of fast fibers and an increase in through activation of FABP5/PPAR𝛾 pathway [61].
mitochondrial biogenesis in cardiac muscle, enhancing the Complementary to studies in which PPAR𝛾 activation
incidence of heart failure and thrombosis in these patients induces neuronal differentiation, recent evidence suggests an
[53]. In addition, the use of pioglitazone in nondiabetic important role of PPAR𝛾 in neuronal polarity [61]. Studies
patients with AD showed a 28.6% of increase in peripheral made on hippocampal neurons indicated that activation of
edema compared to patients treated with placebo [54]. PPAR𝛾 by TZDs drugs enhanced axonal growth [61]. This
effect on axonal growth was accompanied by an increase in
PPAR𝛾 expression and was completely prevented by the use
3. The Role of PPAR𝛾 in Neuronal
of GW9662, a specific PPAR𝛾 antagonist [61]. The enhanced
Development axonal growth induced by PPAR𝛾 activators was prevented
3.1. PPAR𝛾 and Neuronal Stem Cells. Recent evidence sug- by SP 600125, an inhibitor of c-Jun N-terminal kinase (JNK),
gests that PPAR𝛾 could have a potential role in neuronal indicating that the effect of PPAR𝛾 on neuronal polarity was
development [55]. In physiological conditions PPAR𝛾 expres- through the activation of JNK pathway [61].
sion was found in embryo mouse brain and in neuronal stem Finally, the effects of PPAR𝛾 activation have been also
cells (NSCs) [55]. In contrast, extremely low levels of PPAR𝛾 studied in AD mice model that expressed apolipoprotein
were observed in adult mouse brain [55]. More important, (Apo-E4) [64]. Apo-E4 is a major genetic risk factor for
PPAR𝛾 agonists promoted oligodendrocyte differentiation AD and exerts neuropathological effects through multiple
of mouse NSCs, by modulating expression of differentia- pathways, including reduction of dendritic spine density and
tion genes [56]. Moreover, activation of PPAR𝛾 induced mitochondrial dysfunction [65]. Apo-E4 fragments are neu-
expression of neurogenic differentiation factor (Neurod1), a rotoxic and cause neurodegeneration and behavioral deficits
member of the basic helix-loop-helix (bHLH) transcriptional in transgenic mice [66]. In this context, Brodbeck et al.
factor that plays a role in the development of nervous and studied the effects of rosiglitazone on dendritic spine density
endocrine systems [56]. These studies in Neurod1-null mice in AD mice that expressed Apo-E4 [64]. Treatment with
exhibited behavioral abnormalities due to a reduction in the rosiglitazone significantly increased dendritic spine density
number of sensory neurons [56]. Thus, the upregulation of in a dose-dependent manner in cultured cortical neurons
selective differentiation factors could be a mechanism by from wild type mice [64]. This effect was prevented by
which PPAR𝛾 agonists promote differentiation of NSCs. GW9662, suggesting that rosiglitazone exerts this effect by
It has been suggested that activation of PPAR𝛾 could be an activating the PPAR𝛾 [64]. Furthermore, dendritic spine den-
interesting therapeutic target against AD [17, 19]. In this con- sity was significantly decreased in cortical cultures obtained
text, Cannabidiol (CBD), a Cannabis derivative, has attracted from AD Apo-E4 mice, and treatment with rosiglitazone
much attention because of its promising neuroprotective rescued this detrimental effect [64].
properties [57]. New studies suggest that neuroprotective
effects of CBD could be mediated through PPAR𝛾 pathway
[57]. Interestingly, due to its interaction with PPAR𝛾, CBD
4. The Role of PPAR𝛾 in Pain Signaling
was able to stimulate hippocampal neurogenesis [57], indi- Several studies using experimental models have showed that
cating that CBD may exert protective functions through an administration of PPAR ligands reduces inflammation, sug-
increase of neuronal population by the activation of PPAR𝛾 gesting their possible use for treating human inflammatory
[57]. and neuropathic pain [67]. Earlier in 1995, a prominent
expression of PPARs in the thalamus was reported, particu-
3.2. PPAR𝛾 Activation Induces Neuronal Differentiation. An larly in the posterior part of the ventral medial nucleus, a site
important role of PPAR𝛾 in the differentiation of neuronal responsive to pain and cold stress, suggesting the possibility
6 PPAR Research

that PPARs might play a role in modulating response to PPARs ligands

thermal and pain sensations [68].
Further studies reported that the treatment with TZDs
drugs, such as rosiglitazone and pioglitazone, prevented PPAR𝛾
myelin loss, reduced neuropathic pain, and improved motor
function recovery after spinal cord injury [69]. In addi-
tion, Ajulemic acid, which has a potent analgesic and anti-
inflammatory activity, directly interacts with PPAR𝛾 suggest- Mitochondrial Oxidative Calcium Memory
ing that this may be a pharmacologically relevant receptor for dysfunction stress stress impairment
this compound and a potential target for drug development
in the treatment of pain [70]. In addition, new studies have
suggested PPAR𝛾 as a new target for treating chronic pain
[71, 72]. Thus, the expression and function of PPAR𝛾 in spinal Neuroprotection
cord were reported [71]. Moreover, intrathecal administration
of rosiglitazone reduced allodynia (increased sensitivity to Figure 2: Activation of PPAR𝛾 improves neuronal health. Several
pain from a stimulus that normally does not provoke pain) neurodegenerative diseases showed clear deficiencies in mitochon-
and hyperalgesia (increased sensitivity to pain from a stimu- drial function, oxidative stress, and memory impairment. Activation
of PPAR𝛾 by natural ligands or TZDs could prevent these neurode-
lus that normally provokes pain) in the spared nerve injury
generative changes mainly improving mitochondrial function and
(SNI) mouse model of neuropathic pain [71]. These studies increasing antioxidant capacity in neurons.
suggest that new or current drugs that targeted spinal PPAR𝛾
may yield important therapeutic effects for neuropathic pain
[71]. Also it was reported that pioglitazone administration
reduced tactile allodynia and thermal hyperalgesia in partial a possible therapeutic use against neurodegenerative dis-
sciatic nerve ligation (PSL), a study model for neuropathic eases (Figure 2). Concomitantly, studies of PPAR𝛾 activation
pain [73]. PSL-induced upregulation of TNF𝛼 and IL-6 showed important effects against oxidative stress, mitochon-
was suppressed by pioglitazone treatment, indicating that drial dysfunction, and apoptosis in several cells models that
pioglitazone alleviates neuropathic pain through attenuation resemble AD, HD, ALS, and SCI. Also, a large part of this
of proinflammatory cytokine upregulation by PPAR𝛾 [73]. evidence was corroborated in mice models for each of these
Also, systemic administration of TZDs reduces peripheral neurological disorders, and additionally PPAR𝛾 activation
inflammation in vivo suggesting that pharmacological acti- improved cognitive decline observed in several neurodegen-
vation of PPAR𝛾 in the brain rapidly inhibits local edema erative diseases. Moreover, the effects of PPAR𝛾 ligands on
neuroinflammation in animal models suggest their possible
and the spinal transmission of noxious inflammatory signals
use for treating human inflammatory pain and neuropathic
[74]. Interestingly, it was showed that PPAR𝛾 is crucial for
pain.
coupling ibuprofen to RhoA inhibition and subsequently
Altogether these observations suggest an important role
induces neurite growth in neurons, providing additional
for PPAR𝛾 in maintaining normal function of the brain and
therapeutic targets to the disorders characterized by RhoA
preventing neuronal damage induced by stressors and aging.
activation, including spinal cord injury and AD [75]. It was
also reported that rosiglitazone attenuates postincisional pain
by regulating macrophage polarization [76] and alleviated Conflict of Interests
the development of inflammatory pain, possibly through
regulating macrophage infiltration [77]. These observations The authors declare no conflict of interests.
suggest that PPAR𝛾 signaling in macrophages may be a
potential therapeutic target for the treatment of acute pain
development [77]. Finally, oral or intraperitoneal admin- Acknowledgments
istration of pioglitazone prevents multiple behavior sings This work was supported by FONDECYT no. 1140968 (RAQ),
of somatosensory hypersensitivity [72]. Thus, pioglitazone grant of Vicerrectorı́a de Investigación, Pontificia Universi-
reduces spinal glial and stimulus-evoked p-ERK activation dad Católica de Chile (VRI, PUC) (RAQ), PAI 79100009
and reduced neuropathic pain [72]. (EU), and FONDECYT no. 11110136 (EU).
5. Conclusions
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