Oral administration of a novel lipophilic PPARδ agonist is not neuroprotective after rodent cerebral ischemia

Peroxisome proliferator-activated receptors are regulators of inflammatory signaling. This has fostered hope that PPAR agonists might have neuroprotective potential. We hypothesized that PPARδ activation by the novel orally administered lipophilic PPARδ agonist SAR145 may improve short- and long-term outcome after focal brain ischemia. We induced ischemia by transient filamentous middle cerebral artery occlusion (MCAo) in 227 C57BL/6 mice and administered SAR145 in varying doses and time windows post-injury. Outcome was assessed by three functional tests and histologically determining ischemic lesion sizes. In a second experiment, we tested SAR145 treatment in 40 PPARδ-knockout mice using the same procedures. Three independent groups treated with 10 mg/kg bodyweight SAR145 directly after filament removal showed a mean reduction in lesion sizes of 18 +/- 10% compared to vehicle-treated groups. We did not observe a consistent improvement in the long-term functional outcome by SAR145-treatment. PPARδ-knockout mice showed a significantly higher mortality after MCAo. As expected, we did not find a reduction of lesion size by SAR145-treatment in PPARδ-knockout mice. In summary, we found no evidence of a long-term neuroprotective effect of post-injury SAR145 treatment in cerebral ischemia. However, PPARδ appears to play a pathophysiologic role in acute infarct development and overall mortality after brain ischemia

IFN-γ Signaling to Astrocytes Protects from Autoimmune Mediated Neurological Disability

<div><p>Demyelination and axonal degeneration are determinants of progressive neurological disability in patients with multiple sclerosis (MS). Cells resident within the central nervous system (CNS) are active participants in development, progression and subsequent control of autoimmune disease; however, their individual contributions are not well understood. Astrocytes, the most abundant CNS cell type, are highly sensitive to environmental cues and are implicated in both detrimental and protective outcomes during autoimmune demyelination. Experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ) receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB) integrity or the composition of the acute CNS inflammatory response. Nevertheless, increased demyelination at peak acute disease in the absence of IFN-γ signaling to astrocytes correlated with sustained clinical symptoms. Following peak disease, diminished clinical remission, increased mortality and sustained astrocyte activation within the gray matter demonstrate a critical role of IFN-γ signaling to astrocytes in neuroprotection. Diminished disease remission was associated with escalating demyelination, axonal degeneration and sustained inflammation. The CNS infiltrating leukocyte composition was not altered; however, decreased IL-10 and IL-27 correlated with sustained disease. These data indicate that astrocytes play a critical role in limiting CNS autoimmune disease dependent upon a neuroprotective signaling pathway mediated by engagement of IFN-γ receptors.</p> </div

Astrocytes regulate IL-1, CCL5 and TNF mRNA during acute EAE.

<p>Relative gene expression in spinal cord from GFAPγR1Δ (average clinical score = 3.9) and wt mice (average clinical score = 3.1) during acute disease (day 18 p.i.) determined by qRT-PCR. Representative of 2 experiments (n = 3 – 4 mice/group) analyzed in triplicate. *p<0.05 comparing wt and GFAPγR1Δ mice.</p

IFN-γ signaling regulates astrocyte activation within grey matter during chronic EAE.

<p>Cross section of spinal cord grey matter from wt (upper panel) and GFAPγR1Δ mice (lower panel) during chronic disease (day 35 p.i.). Grey matter regions shown are distinct from areas of demyelination. Data are representative of 3 separate experiments with 3 – 4 individuals per experiment and 6 cross sections per spinal cord and 2 separate experiments in which the spinal cords were sectioned longitudinally.</p

Sustained demyelination, axonal loss and astrocyte activation during chronic disease.

<p>Cross section of spinal cord from wt (upper panels) and GFAPγR1Δ mice (lower panels) during chronic disease (day 35 p.i.). Inflammation (HE), demyelination (LFB), axonal damage and loss following visualization with mAb SMI31 and SMI32 (SMI), GFAP expression and hypertrophy of astrocytes (GFAP) in wt and GFAPγR1Δ mice. Data are representative of 3 separate experiments with 3 – 4 individuals per experiment and 6 cross sections per spinal cord.</p