A therapeutic role for cyclooxygenase‐2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis

Pompl, Patrick; Ho, Lap; Bianchi, Mauro; McManus, Terence; Qin, Weiping; Pasinetti, Giulio Maria

doi:10.1096/fj.02-0876fje

Cited by 139 publications

(109 citation statements)

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“…Amyotrophic lateral sclerosis (ALS) is characterized by a loss of motor neurons associated with a robust glial response including microglial and astrocytic activation and the upregulation of COX-2 and iNOS in the spinal cord (89). Similar pathological features can be observed in the ALS animal model, transgenic mice overexpressing SOD1-G93A (117). Oral treatment of these mice with pioglitazone decreased motor neuronal loss and muscular atrophy and prevented microglial activation at the degenerative sites (88).…”

Section: Ppar-gamma Effects In the Cnsmentioning

confidence: 86%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

374

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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Section: Ppar-gamma Effects In the Cnsmentioning

confidence: 86%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

374

246

View full text Add to dashboard Cite

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“…COX-2 expression and activity are also induced in neurons in vivo in acute paradigms of excitotoxicity (Yamagata, 1993;Adams et al, 1996;Miettinen et al, 1997), and can promote injury in cerebral ischemia (Nogawa et al, 1997;Nakayama et al, 1998;Dore, 2003) and possibly in neurodegenerative disorders such as ALS (Drachman et al, 2002;Pompl, 2003), Parkinson's disease (Feng, 2002;Teismann, 2003), and Alzheimer's disease (Pasinetti, 1998). Thus, COX-2 activity and prostaglandin production function physiologically in neuroplasticity and pathologically in promoting neuronal injury, depending on the magnitude of COX-2 induction.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia

McCullough¹,

Wu²,

Haughey³

et al. 2004

J. Neurosci.

338

375

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The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE 2 , a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE 2 exerts its downstream effects by signaling through a class of four distinct G-proteincoupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE 2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMPdependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE 2 receptor subtype in brain that may provide a target for therapeutic intervention.

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“…Vgf is a component of the chromogranin/secretogranin family 47, 48 actively involved in amyotrophic lateral sclerosis (ALS) neuroprotection 49. Because it is described that declined levels of this bioactive peptide (Vgf) could promote neurodegeneration 50, further investigation of these aspects is required.…”

Section: Discussionmentioning

confidence: 99%

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

et al. 2016

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SummaryAim and methodsDifferent types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells. With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.ResultsThe synthetic cannabinoid agonist WIN55212.2 at 1 μM increased the myelin basic protein mRNA and protein expression in vitro. During cuprizone‐induced acute demyelination, the administration of 0.5 mg/kg WIN55212.2 confers more myelinated axons, increased the expression of retinoid X receptor alpha, and declined nogo receptor expression. Controversially, 1 mg/kg of the drug increased the number of demyelinated axons and reduced the expression of nerve growth factor inducible, calreticulin and myelin‐related genes coupling specifically with a decrease in 2′,3′‐cyclic nucleotide 3′ phosphodiesterase expression.ConclusionThe cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro. Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone‐induced demyelination, while 1 mg/kg aggravates the demyelination process.

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A therapeutic role for cyclooxygenase‐2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis

Cited by 139 publications

References 18 publications

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

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A therapeutic role for cyclooxygenase‐2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis

Cited by 139 publications

References 18 publications

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Neuroprotective Function of the PGE2EP2 Receptor in Cerebral Ischemia

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

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Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia