If it's on your mind and it has to do with multiple sclerosis in any way, post it here.


Postby OddDuck » Sat Mar 19, 2005 5:00 am

I found a pretty good biological description of PPAR that I thought I would post, in case some folks wanted to find out a bit more about it.

http://www.answers.com/topic/peroxisome ... d-receptor

peroxisome proliferator-activated receptor

In cell biology, peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor isoforms that exist across biology. Originally identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes in cells, they are intimately connected to the cellular metabolism (carbohydrate, lipid and protein) and cell differentiation. They are transcription factors.


Three types of PPARs have been identified: alpha, gamma and delta (beta).

• α (alpha) - expressed in kidney, heart, muscle, adipose tissue, and others.

• γ (gamma) - although transcribed by the same gene, this PPAR exists in three forms:
o γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas and spleen.
o γ2 - expressed mainly in adipose tissue (30 aminoacids longer)
o γ3 - expressed in macrophages, large intestine, white adipose tissue.

• δ (delta) - expressed in many tissues but markedly in brain, adipose tissue and skin.


PPARs were discovered during the search of a molecular target for a group of agents then referred to as "peroxisome proliferators", as they increased peroxisomes in rodent liver tissue, apart from improving insulin sensitivity. These agents, pharmacologically related to the fibrates, had been discovered in the early 1980s. When it turned out that PPARs played a much more versatile role in biology, the agents were in turn termed "PPAR ligands". The best-known PPAR ligands are the thiazolidinediones; see below for more details.

What happened to PPARβ (beta)?

After PPARδ (delta) was identified in humans in 1992, it turned out to be identical to the PPARβ (beta) previously described during the same year in other animals (Xenopus). The name PPARδ is generally used to the exclusion of PPARβ.

Physiological function

All PPARs dimerize with the retinoid X-receptor (RXR) and bind to specific regions on the DNA, termed PPREs (peroxisome proliferator response elements). The DNA consensus sequence is AGGTCAXAGGTCA with X being a random nucleotide. Generally, this sequence occurs in the promotor region of a gene, and when the PPAR is activated, transcription is increased (a number of genes is, however, suppressed by PPARs). The RXR also forms a heterodimer with a number of other receptors: the vitamin D receptor and the thyroid hormone receptor.

The function of PPARs is modified by the exact shape of their ligand-binding domain (see below) and by a number of co-activators and co-repressors, the presence of which can stimulate or inhibit receptor function. Insulin appears to be an important cofactor, through activation of the insulin receptor.

The ligands for the PPARs are free fatty acids and eicosanoids. PPARγ is activated by PGJ2 (a prostaglandin). In contrast, PPARα is activated by leukotriene B4.


The three main forms are transcribed from different genes:

• PPARα - chromosome 22q12-13.1 (OMIM 170998).
• PPARγ - chromosome 3p25 (OMIM 601487).
• PPARδ - chromosome 6p21.2-21.1 (OMIM 600409).

Hereditary disorders of all PPARs have been described, generally leading to a loss in function and concomitant lipodystrophy, insulin resistance and/or acanthosis nigricans. Of PPARγ, a gain-of-function mutation has been described and studied (Pro12Ala) which decreased the risk of insulin resistance; it is quite prevalent (allele frequency 0.03 - 0.12 in some populations). In contrast, pro115gln is associated with obesity. Some other polymorphisms have high incidence in populations with elevated body mass indexes.


All PPARs have a basic structure of functional domains. The most important ones are the DBD (DNA binding domain) and the LBD (ligand binding domain). The DBD contains two zinc finger patterns which bind to the regulator region of DNA when the receptor is activated. The LBD has an extensive secondary structure of several alpha helices (13) and a beta sheet. Natural and synthetic ligands bind to the LBD, activating the receptor.


PPARα and PPARγ are the targets of a number of known medications and are under continuing research for other forms of pharmacological modulation.


PPAR-alpha is the main target of fibrate drugs, a class of amphipathic carboxylic acids (clofibrate, gemfibrozil and others). They are used in cholesterol disorders (generally as an adjunctive to statins) and disorders that feature high triglycerides.


PPAR-gamma is the main target of the drug class of thiazolidinediones, used in diabetes mellitus and other diseases that feature insulin resistance. It is also mildly activated by certain NSAIDs (such as ibuprofen) and indoles. Known inhibitors include the experimental agent GW-9662.

See also
• Thiazolidinedione
• Anti-diabetic drug
• Diabetes mellitus
• Insulin resistance
• Metabolic syndrome


• Berger J, Moller DE. The mechanism of action of PPARs. Annu Med Rev 2002;53:409-35. PMID 11818483.

External links

• PPAR resource (Penn State University).
• PPAR reference outline (Rutgers).
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Postby OddDuck » Sat Mar 19, 2005 5:29 am

Ann Neurol. 2002 Jun;51(6):694-702.

Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis.

Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT.

Department of Anesthesiology, University of Illinois, 11819 West Polk Street, MC519, Chicago, IL 60612, USA. dlfeins@uic.edu

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.

PMID: 12112074 [PubMed - indexed for MEDLINE]

J Neuroimmunol. 2005 Apr;161(1-2):113-22.

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.

Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Slot 510, 4301 West Markham Street, Little Rock, AR 72205, USA.

Peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) and 15-deoxy-Delta(12,14) prostaglandin J(2) (15d-PGJ(2)), have been shown to be effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study aimed to compare the anti-inflammatory actions of three TZDs - rosiglitazone, pioglitazone, and ciglitazone - with those of 15d-PGJ(2) on stimulated mouse microglia and astrocytes. The results show that TZDs and 15d-PGJ(2) are effective in inhibiting production of nitric oxide, the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6, and the chemokine MCP-1 from microglia and astrocytes. However, 15d-PGJ(2) was a more potent suppressor of pro-inflammatory activity than the TZDs. 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.

PMID: 15748950 [PubMed - in process]

I can't help but refer back to how I compared some of the mechanisms of action of desipramine back in June, 2004 to a TZD. What I have highlighted in bold above is part of the reason why I drew the similarities between desipramine and a TZD, in addition to the fact that desipramine also has many "gene therapy" type of properties similar to a TZD. (Hey, I can't help but throw my "pet drug" in there. :wink: )

Of course, there are many studies out there which all say basically the same thing (about TZDs), and I know there is a small clinical trial going on at the University in Chicago right now with a TZD.

What researchers have also claimed is that a PPAR-gamma agonist also inhibits IL12, which is found to be beneficial in MS.

For those of you who are interested in dietary comparisons, Vanderbilt found that what curcumin (i.e. tumeric) does (among other things - see below) that is helpful in MS is that it inhibits IL12.

Just FYI.


J Neuroinflammation. 2005 Feb 25;2(1):8.

Astrocyte production of the chemokine macrophage inflammatory protein-2 is inhibited by the spice principle curcumin at the level of gene transcription.

Tomita M, Holman BJ, Santoro CP, Santoro TJ.

Department of Medicine, University of North Dakota School of Medicine & Health Sciences, 501 North Columbia Road, Grand Forks, ND 58201, USA. mtomita@medicine.nodak.edu.

BACKGROUND: In neuropathological processes associated with neutrophilic infiltrates, such as experimental allergic encephalitis and traumatic injury of the brain, the CXC chemokine, macrophage inflammatory protein-2 (MIP-2) is thought to play a pivotal role in the induction and perpetuation of inflammation in the central nervous system (CNS). The origin of MIP-2 in inflammatory disorders of the brain has not been fully defined but astrocytes appear to be a dominant source of this chemokine.Curcumin is a spice principle in, and constitutes approximately 4 percent of, turmeric. Curcumin's immunomodulating and antioxidant activities suggest that it might be a useful adjunct in the treatment of neurodegenerative illnesses characterized by inflammation. Relatively unexplored, but relevant to its potential therapeutic efficacy in neuroinflammatory syndromes is the effect of curcumin on chemokine production. To examine the possibility that curcumin may influence CNS inflammation by mechanisms distinct from its known anti-oxidant activities, we studied the effect of this spice principle on the synthesis of MIP-2 by astrocytes. METHODS: Primary astrocytes were prepared from neonatal brains of CBA/CaJ mice. The cells were stimulated with lipopolysaccharide in the presence or absence of various amount of curcumin or epigallocatechin gallate. MIP-2 mRNA was analyzed using semi-quantitative PCR and MIP-2 protein production in the culture supernatants was quantified by ELISA. Astrocytes were transfected with a MIP-2 promoter construct, pGL3-MIP-2, and stimulated with lipopolysaccharide in the presence or absence of curcumin. RESULTS: The induction of MIP-2 gene expression and the production of MIP-2 protein were inhibited by curcumin. Curcumin also inhibited lipopolysaccharide-induced transcription of the MIP-2 promoter reporter gene construct in primary astrocytes. However MIP-2 gene induction by lipopolysaccharide was not inhibited by another anti-oxidant, epigallocatechin gallate. CONCLUSION: Our results indicate that curcumin potently inhibits MIP-2 production at the level of gene transcription and offer further support for its potential use in the treatment of inflammatory conditions of the CNS.
PMID: 15733321 [PubMed - as supplied by publisher]

J Immunol. 2002 Jun 15;168(12):6506-13. Related Articles, Links

Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.

Natarajan C, Bright JJ.

Division of Neuroimmunology, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.
PMID: 12055272 [PubMed - indexed for MEDLINE]
Last edited by OddDuck on Sat Mar 19, 2005 5:49 am, edited 1 time in total.
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Postby bromley » Sat Mar 19, 2005 5:38 am


I thought MS was supposed to reduce one's cognitive abilities? Your brain must be growing by the day with all the research you keep doing.

Have the weekend off - bake some cakes, mow the lawn.

All the best


(I do appreciate all your work - you put the ms researchers and scientists to shame. The NMSS should be giving you a retro-spective grant)
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Postby OddDuck » Sat Mar 19, 2005 5:42 am

Good morning, bromley!! :D (Well, it's morning here anyway. Only 6:40 a.m.!) I'm just sitting here sipping tea (green, of course), and thought well, what the heck, I'd post a little from where I left off yesterday.

I think I'm pretty well done. :wink:

BAKE? You mistake me for being "domestic"! HAH! Mow the lawn? You mistake me for being "active". hahahahahahahhaha........

I'd rather just sit here and sip green tea. hehehe.....


EDIT: P.S. Besides, remember, I'm taking levetiracetam too, which fixed my cognitive problems. :wink:
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