Ligands for the peroxisome proliferator-activated receptor-γ and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis

Diab, Asim; Hussain, Rehana Z.; Lovett-Racke, Amy E.; Chavis, Janet A.; Drew, Paul D.; Racke, Michael K.

doi:10.1016/j.jneuroim.2003.11.010

Cited by 112 publications

(85 citation statements)

References 38 publications

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“…Both pioglitazone and rosiglitazone were shown to decrease the infarct volume in rodent focal ischemia models (Shimazu et al, 2005;Sundararajan et al, 2005;Tureyen et al, 2007). The PPAR␥ natural agonist 15-d-PGJ 2 was shown to decrease neurological deficits after experimental intracerebral hemorrhage (Zhao et al, 2006) and disease severity after experimental autoimmune encephalopathy (Diab et al, 2004), and its plasma levels were shown to correlate to the neurological function in stroke patients (Blanco et al, 2005). These studies indicate that TZDs have significant therapeutic potential in neuroinflammatory disorders in addition to diabetes.…”

Section: Discussionmentioning

confidence: 86%

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats

Park

Yi²,

Miranpuri³

et al. 2006

J Pharmacol Exp Ther

213

177

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Thiazolidinediones (TZDs) are potent synthetic agonists of the ligand-activated transcription factor peroxisome proliferatoractivated receptor-␥ (PPAR␥). TZDs were shown to induce neuroprotection after cerebral ischemia by blocking inflammation. As spinal cord injury (SCI) induces massive inflammation that precipitates secondary neuronal death, we currently analyzed the therapeutic efficacy of TZDs pioglitazone and rosiglitazone after SCI in adult rats. Both pioglitazone and rosiglitazone (1.5 mg/kg i.p.; four doses at 5 min and 12, 24, and 48 h) significantly decreased the lesion size (by 57 to 68%, p Ͻ 0.05), motor neuron loss (by 3-to 10-fold, p Ͻ 0.05), myelin loss (by 66 to 75%, p Ͻ 0.05), astrogliosis (by 46 to 61%, p Ͻ 0.05), and microglial activation (by 59 to 78%, p Ͻ 0.05) after SCI. TZDs significantly enhanced the motor function recovery (at 7 days after SCI, the motor scores were 37 to 45% higher in the TZD groups over the vehicle group; p Ͻ 0.05), but the treatment was effective only when the first injection was given by 2 h after SCI. At 28 days after SCI, chronic thermal hyperalgesia was decreased significantly (by 31 to 39%; p Ͻ 0.05) in the pioglitazone group compared with the vehicle group. At 6 h after SCI, the pioglitazone group showed significantly less induction of inflammatory genes [interleukin (IL)-6 by 83%, IL-1␤ by 87%, monocyte chemoattractant protein-1 by 75%, intracellular adhesion molecule-1 by 84%, and early growth response-1 by 67%] compared with the vehicle group (p Ͻ 0.05 in all cases). Pioglitazone also significantly enhanced the post-SCI induction of neuroprotective heat shock proteins and antioxidant enzymes. Pretreatment with a PPAR␥ antagonist, 2-chloro-5-nitro-N-phenyl-benzamide (GW9662), prevented the neuroprotection induced by pioglitazone.Peroxisome proliferator-activated receptor (PPAR) and retinoid X receptor are ligand-activated transcription factors of the nuclear hormone receptor superfamily. Upon ligand binding, PPAR forms a heterodimeric complex with retinoid X receptor that binds to the cis-acting sequences (peroxisome proliferator response element) on DNA to initiate or repress the transcription of target genes (Blanquart et al., 2003). PPAR exists as three isoforms (␣, ␥, and ␦/␤) that control many cellular functions including lipid metabolism, glucose absorption, and cell growth and differentiation (Escher and Wahli, 2000). 15-Deoxy-⌬-12,14-prostaglandin J 2 (15-d-PGJ 2 ) is the natural agonist and thiazolidinediones (TZDs) (troglitazone, ciglitazone, rosiglitazone, and pioglitazone) are potent synthetic agonists of PPAR␥. Of these, troglitazone was removed from the market because of hepatotoxicity, whereas rosiglitazone and pioglitazone are currently ap-

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Section: Discussionmentioning

confidence: 86%

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats

Park

Yi²,

Miranpuri³

et al. 2006

J Pharmacol Exp Ther

213

177

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“…In EAE, a well-established model of immune-mediated demyelination that mimics many aspects of MS, 9cRA has been shown to suppress inflammation. Our work suggests RXR agonists will be of value as a regenerative therapy, filling the unoccupied niche of a treatment for progressive MS [84]. Thus, Targretin and other RXR agonists could conceivably provide an important advance in MS therapy, contributing not only to damage suppression through immunomodulation, but also axon preservation through enhancement of remyelination.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 89%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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“…A licensed RXR agonist, Targretin ® (bexarotene), is already in clinical use for treatment of cutaneous T-cell lymphoma [8]. In experimental autoimmune encephalomyelitis, a well-established model of immune-mediated demyelination that mimics many aspects of MS, 9cR A has been demonstrated to suppress inflammation [9]. Our work suggests that RXR agonists will be of value as a regenerative therapy, filling the unoccupied niche of a treatment for progressive MS.…”

mentioning

confidence: 86%

Retinoid X receptors as a potential avenue for regenerative medicine in multiple sclerosis

Huang

Jarjour

ffrench‐Constant

et al. 2011

Expert Review of Neurotherapeutics

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Ligands for the peroxisome proliferator-activated receptor-γ and the retinoid X receptor exert additive anti-inflammatory effects on experimental autoimmune encephalomyelitis

Cited by 112 publications

References 38 publications

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats

Thiazolidinedione Class of Peroxisome Proliferator-Activated Receptor γ Agonists Prevents Neuronal Damage, Motor Dysfunction, Myelin Loss, Neuropathic Pain, and Inflammation after Spinal Cord Injury in Adult Rats

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

Retinoid X receptors as a potential avenue for regenerative medicine in multiple sclerosis

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