Peroxisome Proliferator-Activated

Receptors (PPARs)

Marvin Boris, MD
Michael Elice, MD
Allan Goldblatt, PA
Woodbury, New York
 TH 1 → TH2
• TUMOR NECROSIS • INTERLEUKIN 4
FACTOR (TNF) • INTERLEUKIN 5
• INTERFERON • INTERLEUKIN 6
GAMMA • INTERLEUKIN 9
• INTERLEUKIN 2 • INTERLEUKIN 10
• INTERLEUKIN 13
 CYTOKINES
• Cytokines are small secreted proteins which
mediate and regulate immunity,
inflammation, and hematopoiesis. They are
produced de novo in response to an immune
stimulus.. Cytokines regulate the intensity
and duration of the immune response by
stimulating or inhibiting the activation,
proliferation, and/or differentiation of various
cells and by regulating the secretion of
antibodies or other cytokines.
 Rationale for new treatments aimed
at IgE immunomodulation
Jeffrey Stokes, MD and Thomas B. Casale, MD

Annals of Allergy, Asthma, & Immunology ©2004;93:212-217

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 PPARS RESPONSIVE
AUTOIMMUNE DISEASES
• Multiple Sclerosis
• Alzheimers
• Crohn’s Disease
• Ulcerative Colitis
• Diabetes Mellitus
• Psoriasis
• Rheumatoid Arthritis
• Autoimmune encephalitis
• Atherosclerosis
• Liver Fibrosis and Cirrhosis
• Metabolic Syndrome
• Atherosclerosis
• Inhibits Angiogenesis ( Cancer Therapy)
 Multiple Sclerosis
•
Effect of pioglitazone treatment in a patient
with secondary multiple sclerosis
Harrihar A Pershadsingh1, 2 , Michael T Heneka2 , Rashmi
Saini1 , Navin M Amin1 , Daniel J Broeske3 and Douglas L
Feinstein4
1Departments of Family Medicine, Kern Medical Center, Bakersfield,
and University of California, Irvine, California, USA
2Department of Neurology, University of Bonn, Bonn, Germany
3Department of Internal Medicine, Kern Medical Center, Bakersfield,
California, USA
4Department of Anesthesiology, University of Illinois, Chicago,
Illinois, USA
Figure 1 Resolution: standard /
high

Axial T1-weighted fluid-attenuated inversion recovery

(FLAIR) MRI images showing confluent demyelination.
MRIs were taken at 10 months (left) and at 18
months (right) after initiation of treatment with
pioglitazone. Similar axial sections are shown for the
two time points.
 Multiple Sclerosis
• Anti-inflammatory and antiproliferative
actions of PPAR-gamma agonists on T
lymphocytes derived from MS patients.J
Leukoc Biol 2004 Mar;75(3):478-85 (ISSN: 0741-5400)Schmidt
S; Moric E; Schmidt M; Sastre M; Feinstein DL; Heneka MT
Department of Neurology, University of Bonn, Germany.

• In summary, the data support the potential

use of PPAR-gamma agonists as
immunomodulatory, therapeutic agents for
autoimmune diseases
 Alzheimers and MS
• Therapeutic potential of peroxisome proliferator-
activated receptor agonists for neurological disease.
Feinstein DL.
Department of Anesthesiology, University of Illinois, Chicago, Illinois
60612,
• PPAR activation can have additional effects upon
cellular physiology, including anti-proliferative and anti-
inflammatory. These effects are observed in many cell
types, including brain glial cells and blood lymphocytes,
cells whose activation contributes to the initiation and
progression of damage occurring in neurological
diseases such as Alzheimer's disease (AD) and multiple
sclerosis (MS).
 Alzheimers Disease (AD)
• Peroxisome proliferator-activated receptor gamma is expressed
in hippocampal neurons and its activation prevents beta-
amyloid neurodegeneration: role of Wnt signaling.
Inestrosa NC, Godoy JA, Quintanilla RA, Koenig CS, Bronfman
M.
Centro FONDAP de Regulacion Celular y Patologia Joaquin V.
Luco, Facultad de Ciencias Biologicas, Pontificia Universidad
Catolica de Chile, Santiago, Chile.
• The molecular pathogenesis of Alzheimer's disease (AD) involves
the participation of the amyloid-beta-peptide (A beta), which plays a
critical role in the neurodegeneration that triggers the disease.
• More important, the fact that the activation of PPAR gamma
attenuated A beta-dependent neurodegeneration opens the
possibility to fight AD from a new therapeutic perspective
 Multiple Sclerosis-Glial Cells
• Peroxisome proliferator-activated receptor-gamma
agonists inhibit the activation of microglia and
astrocytes: Implications for multiple sclerosis.
Storer PD, Xu J, Chavis J, Drew PD.
• These studies suggest that PPAR-gamma agonists
modulate EAE, at least in part, by inhibiting the activation
of microglia and astrocytes. The studies further suggest
that PPAR-gamma agonists may be effective in the
treatment of MS.
 Glial Inflammation in Autism
• Neuroglial activation and neuroinflammation
in the brain of patients with autism.
Vargas DL, Nascimbene C, Krishnan C,
Zimmerman AW, Pardo CA.
Department of Neurology, Johns Hopkins
University School of Medicine, 600 North Wolfe
Street, Baltimore, MD 21287, USA.
• . Immunocytochemical studies showed marked
activation of microglia and astroglia, and
cytokine profiling.
 Colitis
• An open-label trial of the PPAR-gamma
ligand rosiglitazone for active ulcerative
colitis.
Lewis JD, Lichtenstein GR, Stein RB, Deren JJ, Judge TA, Fogt
F, Furth EE, Demissie EJ, Hurd LB, Su CG, Keilbaugh SA, Lazar
MA, Wu GD.
Division of Gastroenterology, Center for Clinical Epidemiology and
Biostatistics, University of Pennsylvania School of Medicine
• CONCLUSIONS: These data suggest that
ligands for the gamma subtype of PPARs may
represent a novel therapy for ulcerative colitis.
 Cancer
• PPARgamma as a Therapeutic Target for Tumor
Angiogenesis and Metastasis.

Panigrahy D, Huang S, Kieran MW, Kaipainen A.

Vascular Biology Program, Children's Hospital,

Department of Surgery, Dana-Farber Cancer Institute,
Harvard Medical School, Boston, Massachusetts, USA.
IMMUNOLOGICAL PROBLEMS IN
AUTISM
• COLITIS
• THYROIDITIS
• DIABETES
• PANDAS
• MYELIN BASIC PROTEIN ANTIBODIES
• ALLERGIES → REGRESSION
• NON SPECIFIC - ↑ PLATLETS, ↑ ESR
• METABOLIC SYNDROME
• MANY OTHERS WE DON’T KNOW
 IV GAMMA GLOBULIN
Aberrant Behavior Checklist - Total Score
80
Mean Total Score and Standard Error of the

70

60

50
Mean

40

30

20

10

0
0 1 2 3 4 5 6
Baseline (0) and Monthly Assessments (1-6)
THERAPY AND EVALUATION
• BASELINE LABS
– Th1 Cytokines- IL2, TNF, Interferon gamma
– Th2 Cytokines-IL 4,5,6,10,13
– Myelin Basic Protein Autoantibodies
– Thyroid autoantibodies

PPARS MEDS- PIOGLITAZONE (Actos) 30 to 60 mg

REPEAT OF BASELINE LABS
ABBERANT BEHAVIORAL NEUROPSYCHOLOGY
TESTS BEFORE AND AFTER ACTOS
 RESPONSE TO ACTOS
• TIME 1-8 Months
• ↑ Cognition
• ↑ Calmness
• ↑ Verbal
• ↓ Diarrhea
• ↓ Aggression
• ↑ Socialization
 RESPONSE TO ACTOS
• Many autistic children who responded to
IVIG regressed after stopping IVIG
• Actos therapy reversed regression in
many of these children and most were
better than with IVIG infusions
The participants’ parents completed the Aberrant
Behavior Checklist (ABC) prior to the
administration of Actos and then at a follow-up
assessment, on average, 12-16 weeks later. There
are five subscales on the ABC, consisting of 58
questions. The subscales are: hyperactivity,
inappropriate speech, irritability, lethargy, and
stereotypy. Each question was rated on a 4-point
scale: 0 = ‘not a problem,’ 1 = ‘the behavior is a
problem but slight in degree,’ 2 = ‘the problem is
moderately serious,’ and 3 = ‘the problem is severe
in degree.’ The ABC has been shown to be a valid
and reliable procedure to evaluate
treatment efficacy (see Aman, Singh, Stewart &
Field, 1985).
The mean scores for four of the five ABC subscales
decreased significantly following the administration
of Actos. These subscales included: hyperactivity,
irritability, lethargy, and stereotypy. There was no
change in inappropriate speech. The baseline and
follow-up mean subscale scores, along with the
standard error of the means, are presented in Figure
1. Two-tailed dependent t-tests yielded: hyperactivity,
t(24)=5.58, p<.01; irritability, t(24)=3.86, p<.01;
lethargy, t(24)=3.38, p<.01; and stereotypy, t(24)=3.21,
p<.01.
 Aberrant Behavior Checklist
Baseline and Follow-Up Scores

25

20
Mean and Standard Error of the Mean

15
Baseline
Follow-up

10

0
Irritability Lethargy Stereotypy Hyperactivity Inappropriate
Speech
Subscales
Three of the five subscales were correlated with
age: hyperactivity, r = .498, t(23)=2.75, p<.05;
irritability, r=.430, t(23)=2.28, p<.05; and lethargy,
r=.464, t(23)=2.51, p<.05. These findings
indicate that the younger participants in this study
benefited more from Actos than the older
participants.
 ACTOS SIDE EFFECTS
• Hyperactivity, Agitation 22/350
• Periorbital edema 9/350
• Weight Gain 34/350
• Abnormal CBCs, Liver Functions 4/350
• Hypoglycemia 0/350
• Hyperinsulin 0/350
 LABATORY DATA
• Cytokines pre and post actos being done at
University of Illinois, Dr. Douglas Feinstein
• ↑ Myelin Basic Protein autoantibodies returned
to normal after actos
• Thyroid autoantibodies normalized in many
children post Actos
• Laboratory data at 1-2 monthly follow-up
intervals have not shown liver, kidney, CBC,
glucose or insulin problems
Elevated cytokine levels in children
with autism spectrum disorder
Cynthia A. Molloy, Ardythe L. Morrowa, Jareen Meinzen-Derr
Kathleen Schleifer, Krista Diengerc,
Patricia Manning-Courtney, Mekibib Altayea and Marsha Wills-Karp

: Children
with ASD had increased activation of
both Th2 and Th1 arms of the adaptive
immune response, with a Th2 predominance,
and without the compensatory increase in the
regulatory cytokine IL-10.
 Elevated cytokine levels in
children
with autism spectrum disorder
• This study compared production of IL-2, IFN-γ, IL-4,
IL-13, IL-5 and IL-10 in peripheral blood mononuclear
cells from 20 children with autism spectrum disorder
to those from matched controls. Levels of all Th2
cytokines were significantly higher in cases after
incubation in media alone, but the IFN-γ/IL-13 ratio
was not significantly different between cases and
controls. Cases had significantly higher IL-13/IL-10
and IFN-γ/IL-10 than controls. Conclusion: Children
with ASD had increased activation of both Th2 and
Th1 arms of the adaptive immune response, with a
Th2 predominance, and without the compensatory
increase in the regulatory cytokine IL-10.
 120%
Actos : Baseline Ratio
100%

80%
60%
40%

20%
0.00
IL6 IL1b IL2 IL4 IL5 TNFa IL10 IL13 IFNg

Actos
3000 40000
Cytokine value (pg/ml)

Baseline
2500
30000
2000

1500 20000

1000
10000
500

0 0
IL6 IL1b IL2 IL4 IL5 TNFa IL10 IL13 IFNg
 CYTOKINE LEVELS

40000
35000
30000
AVG
25000 PRE
20000 ACTOS
15000 AVG
10000 POST
5000 ACTOS
0

a
-g
-6

-2

-4

-5
10
b

lph
-1

-1

N
IL

IL

IL

IL
IL

IF
IL

IL

Fa
TN
 CYTOKINE % REDUCTION POST
ACTOS

120.00%
100.00%
80.00%
60.00%
40.00%
20.00%
0.00%

ha
-g
-6

-2

-4

-5
10
b

3
-1

-1

lp
IL

IL

IL

IL
IL

IF
IL

IL

Fa
TN
 SUMMARY
• PPARs improved autoimmune disease
and clinical behavioral and cognitive
abnormalities in Autistic children
• PPARs have been utilized in multiple
inflammatory and autoimmune diseases
with beneficial results
• In our practice, utilizing PPARs in over 350
children, we have seen minimal side
effects, and none serious