NP031112, a Thiadiazolidinone Compound, Prevents Inflammation and Neurodegeneration under Excitotoxic Conditions: Potential Therapeutic Role in Brain Disorders

Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor γ, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.

• Publication year

  2007

• Venue

  Journal of Neuroscience

• Publication date

  2007-05-23

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.1004-07.2007PMID 17522320PMCID PMC6672766
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• GW9662 substantially attenuated NP031112-induced neuroprotection in vitro and in vivo, supporting mediation through peroxisome proliferator-activated receptor gamma.

  Confidence 0.95

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• NP031112 reduced kainic acid-induced inflammation in the rat hippocampus, including edema detected by T2-weighted magnetic resonance imaging and glial activation, and protected tissue in damaged hippocampal areas.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

• glial activation

  cellular response, observation

  Activation of glial cells used as an indicator of inflammatory response in the damaged hippocampus.

  Aliases: gliosis

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• gw9662

  compound, antagonist

  A pharmacological antagonist used to block peroxisome proliferator-activated receptor gamma signaling in the experiments.

  Aliases: 2-chloro-5-nitrobenzanilide

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• kainic acid

  compound, experimental agent

  An excitotoxic agent used to induce hippocampal injury and seizure-related neurodegeneration in the experimental model.

  Aliases: KA

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• np031112

  compound

  A thiadiazolidinone derivative tested here for anti-inflammatory and neuroprotective activity.

  Aliases: thiadiazolidinone compound

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• peroxisome proliferator-activated receptor gamma

  receptor, nuclear receptor

  A nuclear receptor implicated as the signaling target through which NP031112 may act.

  Aliases: PPAR gamma, PPARγ

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• rat hippocampus

  brain region, animal tissue

  The hippocampal brain region in rats that received NP031112 injection and kainic acid challenge in the in vivo experiments.

  Aliases: hippocampus

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• t2-weighted magnetic resonance imaging

  measurement technique, imaging method

  An MRI sequence used to assess edema formation in the injured hippocampus.

  Aliases: T2-weighted MRI, T2 MRI

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

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