Potential therapeutic effect of pioglitazone on neuromyelitis optica spectrum disorders.

Dr Chan, Koon Ho   (Principal Investigator (PI))

Dr Ng Chun Laam   (Co-Investigator)

24

2021-10-01

1372840

Potential therapeutic effect of pioglitazone on neuromyelitis optica spectrum disorders.

Aquaporin-4, Autoantibodies, Autoimmunity, Neuroinflammation, Neuromyelitis optica, Pioglitazone

Others - Medicine, Dentistry and Health

08192726

Health and Medical Research Fund - Full Grant

2020

On-going

Objectives: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune inflammatory demyelinating diseases of the CNS, causing blindness, paraplegia and even mortality. Binding of the pathogenic aquaporin-4 autoantibodies (AQP4-IgG) to astrocytic AQP4 leads to astrocytopathy, demyelination and neuronal injury. Recently, NMOSD lesion development has been shown to depend on an astrocytes-microglia crosstalk. Pioglitazone, a PPARϒ agonist, is an approved drug for type-2 diabetes. Interestingly, it exerts neuroprotective effects through suppressing microglia activation in animal models of CNS insults. We aim to investigate the therapeutic effect of pioglitazone on NMOSD. Hypothesis to be tested: Pioglitazone ameliorates AQP4-IgG-induced motor impairments and spinal cord pathologies via suppressing microglia activation and neuroinflammation through PPARϒ signaling in mice. Design and subjects: Effects of pioglitazone on motor impairments and spinal cord pathologies in mice which received AQP4-IgG. Study instruments: In vivo imaging system, confocal microscope and flow cytometer. Interventions: Preventive and therapeutic pioglitazone. Main outcome measures: Disease progression will be assessed in vivo imaging of spinal cord inflammation and demyelination. Motor impairments will be examined by beam walking test. Spinal cord pathologies and microglia activation will be studied by immunofluorescence and morphometric analysis. Proinflammatory cytokine levels will be measured by ELISA. Signaling mechanism of pioglitazone will be studied by PPARϒ antagonist GW9662. Data analysis: Data will be analyzed by ANOVA. Expected results: Pioglitazone ameliorates AQP4-IgG-induced motor impairments and spinal cord pathologies. It suppresses microglia activation and proinflammatory cytokine levels. Pioglitazone enhances PPARϒ expression and its protective effect is eliminated by PPARϒ antagonist.