Volume 5, Number 1, 2003
Douglas L. Feinstein, Ph.D
Diabetes Technology & Therapeutics
Activation of peroxisome proliferator-activated receptors (PPARs) mediates the insulin-sensitizing effects of thiazolidinediones used for treatment of type 2 diabetes, owing to changes in the transcription and expression of genes influencing carbohydrate and lipid metabolism. However, 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). In view of the need for development of additional therapeutic options, several recent studies have tested the possibility that PPAR agonists would be neuroprotective in these diseases. This paper will summarize data from cell culture experiments and from studies in animal models, demonstrating that PPARg agonists can exert neuroprotective effects, thereby providing the basis for the design of clinical trials to test the safety and efficacy of thiazolidinediones in neuroinflammatory conditions such as AD and MS.
There has been a recent appreciation that peroxisome proliferator-activated receptors (PPARs) and their ligands may play an important role in brain physiology as well as in pathological conditions of the central nervous system (CNS). While a handful of early reports described expression patterns of PPAR mRNAs and proteins in brain,1–3 in the past 2 years an increasing number of studies have reported on the effects of PPAR agonists in animal models of neurological damage and disease, including Alzheimer’s disease4 (AD), multiple sclerosis5 (MS), Parkinson’s disease,6 and the excitatory damage that occurs in stroke.7 In addition, several studies have described the ability of PPAR agonists to reduce glioma and astrocytoma cell growth,8,9 to induce oligodendrocyte differentiation and myelin gene expression,10 and to promote neurite extension.11 Other studies have described anti-proliferative and proapoptotic effects of PPARg ligands on T cells,12,13 whose activation has been shown to be key to the initiation and clinical progression of demyelinating diseases such as MS.14 Together, these additional “insulin-independent” properties and functions of PPAR agonists and activation have sparked a rapidly increasing interest in their potential therapeutic use for diseases and damage of the CNS.
The basis for interest in PPAR research within the CNS stems from several interrelated areas of research, including epidemiological studies of the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in AD (see below), the anti-proliferative effects of PPAR agonists on several cell types including T cells, and the demonstration that PPAR activation can have other long-lasting effects other than upon glucose and lipid metabolism. In this regard, several reports demonstrated that activation of PPARg exerted anti-inflammatory effects in a variety of cell types, including brain glial cells. Thus, Ricote et al.15 and Jiang et al.16 first showed in macrophages that PPARg agonists reduced expression of tumor necrosis factor-a and of the inducible form of nitric oxide synthase (iNOS), both agents known to contribute to inflammatory damage in neurologic diseases including AD and MS. Subsequently, others found that PPARg agonists could reduce inflammatory responses in brain glial cells and neurons17–19 (reviewed by Landreth and Heneka4). Other in vitro studies showed that inflammatory activation of brain glial cells was attenuated by NSAIDs20,21; however, in several studies the concentrations of NSAIDs needed to observe inhibitory effects were higher than the levels needed to inhibit cyclooxygenase 2 (COX-2), but instead were closer to the levels at which NSAIDs bind to and activate PPARg.19
Several studies of the effects of PPARg agonists on brain glial cell activation have been carried out using the natural ligand prostaglandin (PG) J2, which was shown to block microglial and astroglial activation by bacterial endotoxin. 18,22 However, it was found that PGJ2 was unable to activate a PPAR reporter gene transfected into a glial cell line,18 suggesting that its effects were not mediated via PPARg activation. Subsequent studies by other groups have revealed that PGJ2 and other cyclopentenone PGs directly bind to and inactivate IkB kinase, the enzyme responsible for phosphorylation and thence degradation of the IkB protein, a necessary step for nuclear factor (NF) kB activation. 23 Thus studies using PGJ2 to evaluate a role for PPARg activation must be interpreted carefully, and do not necessarily implicate a role for PPAR activation in mediating anti-inflammatory effects.
In contrast, increasing studies using selective PPAR agonists confirm an anti-inflammatory role for PPAR activation in glial and neuronal cells. Thus, Fitch et al.24 showed that PPARg agonists (including ciglitazone) prevented macrophage and astroglial activation in an in vitro model of glial scarring and progressive damage increase (cavitation), and subsequently Combs et al.25 that these agonists reduce microglial activation by aggregated amyloid beta peptide (Ab). These authors have also reported that PPARa agonists also exert anti-inflammatory effects on Ab-stimulated macrophages.26 In our studies we found that the inflammatory responses of neurons in vitro19 were blocked by ibuprofen or indomethacin but only at high concentrations, as well as with PGJ2. Similar findings have been reported recently in which ciglitazone and troglitazone were shown to prevent lipopolysaccharide (LPS)-induced neuronal death.27 We also showed in vivo28 that the neuronal inflammatory damage induced by intracerebellar injection of LPS and interferon (IFN) was prevented by selective PPARg agonists (including troglitazone and ibuprofen) but was not attenuated by the selective COX-2 inhibitor NS398.
AD is a progressive, degenerative disease of the brain, and the most common form of dementia. Approximately 4 million Americans have AD, with roughly 10% of persons over 65 and 50% of those over 85 afflicted. The areas of the brain that control memory and cognition are affected first, but with disease progression cells in other brain regions die. The duration of AD varies from 3 to 20 years, and eventual extensive neuronal loss leads to death. There are currently four drugs approved by the Food and Drug Administration for treatment of AD, all of which are cholinesterase inhibitors. These drugs prevent breakdown of acetylcholine, and about half of the people who take cholinesterase inhibitors experience some improvement in cognitive symptoms.
In view of the fact that inflammatory responses are an important component in AD,29 as indicated by the presence of inflammatory molecules and of activated glia, anti-inflammatory strategies are now being considered for preventative and therapeutic interventions. The possibility that PPARs could play a protective role in AD stems from reports demonstrating protective effects of NSAIDs in AD. Rogers et al.30 showed that a subset of NSAIDs are effective in reducing AD risk, and that the risk and onset of AD were significantly decreased in those patients taking ibuprofen or indomethacin. Subsequent epidemiological studies have confirmed the therapeutic benefits of NSAIDs in AD.31 However, the molecular basis for those effects was not established; instead it was hypothesized that the wellknown property of NSAIDs to inhibit COX-2 was involved. Based on this knowledge, small clinical trials of COX-2-specific inhibitors were designed, with several already carried out32; however, the results from those trials do not support the hypothesis that inhibition of COX- 2 accounts for NSAID effects. The findings of Lehman et al.33 that NSAIDs also bind to and activate PPARg therefore raised the possibility that PPAR activation played a role in these observed neuroprotective effects of NSAIDs.
A more comprehensive review of the potential use of PPAR agonists for treatment of AD has recently been reviewed.4
MS is a chronic, autoimmune disease of the CNS.34 The exact causes of MS are unknown, but it is accepted to be an autoimmune T cellmediated disease, influenced by genetic background and geographic location, and having possible viral involvement. There are between 350,000 and 500,000 people diagnosed with MS in the United States, and an estimated 2.5 million worldwide. MS has traditionally been classified into four main subtypes. Relapsing-remitting MS (RRMS) is characterized by partial or total recovery after attacks. From 70% to 75% of people with MS initially begin with a relapsing- remitting course. Secondary progressive MS (SPMS) initiates as RRMS, which becomes steadily progressive, although attacks and partial recoveries may continue to occur. Of the 70–75% who start with RRMS, over 50% will develop SPMS within 10 years, and 90% within 25 years. Primary progressive MS (PPMS) is characterized by a progressive course from onset, in which symptoms generally do not remit. Fifteen percent of people with MS are diagnosed with PPMS. Progressive relapsing MS (PRMS) is a progressive course from the outset, and also characterized by acute attacks. PRMS is relatively rare, accounting for less than 10% of people with MS.
There are currently five different products approved by the Food and Drug Administration as disease-modifying treatments for MS.35–37 All are provided by injection (subcutaneous or intramuscular), and only one (Novantrone) is approved for SPMS. The IFNb drugs (Betaseron, Rebif, Avonex)38–41 reduce inflammation, decrease relapse rate, increase the time between attacks, decrease the severity of attacks, and decrease the number of accumulated lesions seen on magnetic resonance imaging. However, these drugs are only effective in about 30% of patients. Glatiramer acetate (Copaxone)42 is a copolymer of four amino acids that resembles a portion of myelin basic protein, and also decreases the frequency and severity of attacks. It is believed to act by suppressing T cell function. Mitoxantrone (Novantrone) 43,44 is a relatively nontoxic chemotherapy agent that slows disease progression and reduces the number of relapses by suppressing T cell activation. It is approved for the secondary progressive and relapsing-remitting forms of MS. However, it is used for a limited period of time and with a limited total number of doses owing to accumulated cardiotoxic effects.
With the findings that NSAIDs, and then PPAR agonists, could prevent inflammatory activation of glial cells, and in view of the fact that some agonists also reduced T cell activation, we tested the possibility that PPARg agonists would ameliorate the development of clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS that is commonly used to study pathogenic mechanisms and to test possible therapeutic interventions. In our studies we used the selective PPARg thiazolidinedione agonists pioglitazone and rosiglitazone and the tyrosine-based compound GW347845.5 Using active immunization with an encephalitogenic peptide of the myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice, we found that pioglitazone (provided orally in the chow at 100 ppm, thus providing a daily dose of roughly 10 mg/kg) reduced the incidence of disease (from 93% to 33%), and in the 33% of mice that became ill the severity of disease was attenuated. Protective effects in this model were also seen with rosiglitazone and GW- 347845, suggesting that activation of PPARg was involved. In a second EAE model, in which B10.PL mice were immunized with myelin basic protein to develop a relapsing-remitting form of disease, pioglitazone treatment increased the magnitude of the remissions, prevented relapses, and induced complete remission in some animals. Importantly, in experiments in which the mice were allowed to first become ill, treatment with pioglitazone could induce remissions. The effects on clinical signs were accompanied by reduced inflammation in brain, and by reduced T cell activation.
The effects of PPARg agonists on the clinical and histological development of EAE have been reported in three other studies. One45 used a similar paradigm as ours, and examined the effects of the thiazolidinedione troglitazone on the development of disease in C57B6 mice immunized with the same MOG peptide. Treatment of mice with troglitazone (daily, 100 mg/kg by gavage) modestly reduced the average maximal clinical score, but had no effect on disease incidence, T cell proliferation, IFNg production, or spinal cord iNOS mRNA levels. A second study46 examined the effects of the natural ligand PGJ2 on EAE in B10.PL mice. PGJ2 treatment delayed the appearance of clinical signs and reduced the severity of the disease. The agonist also reduced the proliferation of and cytokine production from T cells. However, as discussed above, interpretation of those results is confounded by the fact that PGJ2 can directly inhibit IkB degradation. Thus, although treatment was beneficial, it is not clear if those effects were mediated via PPARs.
The most recent study47 reported the effects of PGJ2 as well as the more selective ligand ciglitazone in EAE in SJL mice. In that study the PPARg agonists reduced clinical signs of the disease, reduced interleukin-12 production, and increased differentiation of antigen-specific Th1 cells (which would reduce overall T cell activation).
MOLECULAR MECHANISMS OF NEUROPROTECTIVE ACTIONS
The molecular mechanisms by which PPARg activation can exert neuroprotective effects need to be determined. The fact that inflammatory gene activation contributes to neurological damage, and that a principal activator of such expression is transcription factor NFkB, suggests that modulation of NFkB activation may be involved. In this regard, the findings that PPARg activation can increase expression of the inhibitory IkB protein, the natural inhibitor of NFkB, could account for some of its effects, particularly since it has been shown that pioglitazone can increase brain IkB expression. 5 PPARg activation has also been shown to induce a heat shock response,48 a basic cell and tissue mechanism that has been shown to provide neuroprotection in stroke and models of neuro-inflammatory disease, including MS. As mentioned above, it has been reported that PPARg activation reduces the activation and proliferation of T cells, which could contribute to protective effects in diseases where lymphocyte infiltration into the CNS occurs. Finally, the fact that PPAR agonists increase glucose uptake in certain cell types raises the possibility that these drugs could influence glial or neuronal energy metabolism in a similar manner, thus providing needed energy supplies under conditions (such as may occur in stroke, AD, or MS) where blood flow or glucose supplies are limited.
The finding that PPAR agonists can carry out additional actions aside from increasing glucose utilization and insulin sensitivity has opened open new avenues of research that could have important therapeutic consequences. Based on the fact that PPAR activation can have anti-inflammatory effects, several clinical trials have been implemented to test if PPAR agonists could be useful in colitis,49 bowel disease,50 and psoriasis.51 Findings that the same agonists can reduce T cell activation suggest that other T cell-mediated diseases could be responsive to similar treatment. In view of the importance that inflammatory responses as well as T cell functions play in neurological disease and trauma, it is not surprisingly that PPAR agonists are now being considered for several CNS indications. In addition to studies involving AD and MS, it should be noted that studies to evaluate a potential protective role of PPAR and their agonists in other neurological conditions are being pursued, including models of stroke, Parkinson’s disease, brain tumors including glioma and astrocytoma, excitotoxic injury, AIDS dementia, and regulation of cerebral blood flow and metabolism. At the clinical level, the design of phase 1 or 2 trials to test safety and efficacy of pioglitazone in AD and MS has already started, and initial results may be available in the near future.
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Douglas L. Feinstein, Ph.D.
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University of Illinois
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