PET Imaging Study of S1PR1 Expression in a Rat Model of Multiple Sclerosis

Abstract

Purpose Upregulation of sphingosine-1-phosphate receptor 1 (S1PR1) expression in multiple sclerosis (MS) lesions is associated with neuroinflammatory response. This study investigated the correlation between neuroinflammation and S1PR1 expression in the spinal cord of an experimental autoimmune encephalomyelitis (EAE) rat model of MS, using the S1PR1 positron emission tomography (PET) radiotracer [11C]TZ3321. Procedures MicroPET imaging studies of [11C]TZ3321 were performed to measure uptake of [11C]TZ3321 in the spinal cord of EAE rats. Immunohistochemical staining was performed to confirm the overexpression of S1PR1 and other inflammatory biomarkers. Results MicroPET imaging demonstrated a 20–30 % increase in [11C]TZ3321 uptake in the lumbar spinal cord of EAE rats versus sham controls at 35–60 min post injection. The increased uptake of [11C]TZ3321 was correlated with the overexpression of S1PR1 in the lumbar spinal cord of EAE rats that was confirmed by immunohistochemical staining. Upregulated S1PR1 expression was associated with glial cell activation and immune cell infiltration. Conclusions MicroPET imaging modality with a specific radioligand [11C]TZ3321 is able to assess the expression of S1PR1 in EAE rat lumbar spinal cord. This may provide a new approach to the assessment of neuroinflammatory response in MS and other inflammatory diseases.

Pharmacologic characterizations of a P2X7 receptor-specific radioligand, [11C]GSK1482160 for neuroinflammatory response

“…5B&C). Similar Iba-1 positive cells distribution trend was found within both white matter and grey matter, which was consistent with previous report [21]. In white matter the number of Iba-1 positive cells reached the maximum (9.76 ± 1.19/100 μm 2 ) in EAE-P group then decline to 6.13 ± 1.30/100μm 2 in EAE-R group.…”

“…Neuroinflammation plays a key role in the demyelinating pathogenesis of MS. The rat EAE model of MS includes acute severe neuroinflammation in lumbar spinal cord, with modest demylination, and has been used in our lab for evaluation of radioligands targeting neuroinflammation [21]. Noteably, [ 11 C]GSK1482160 showed 100 times lower binding affinity for the rodent P2X7 receptor versus the human P2X7 receptor (316 nM v.s.…”

“…The EAE rat model was induced according to our published procedure [21]. In brief, female Lewis rats (Charles River Laboratories, Inc., Wilmington, MA), weighing 100–125 g, were randomly divided into 3 groups; sham group (n = 6), EAE-P (peak) group (n = 7) referring to 12–14 days post immunization corresponding to the highest disability score (4.0 – 5.0) in the acute phase of the disease and the EAE-R (auto-remitting) group (n = 4) which was about 4 weeks after immunization when the symptoms had disappeared completely (score 0).…”

Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn’s Disease

“…Inhibition of this signaling by an S1P1R agonist, such as fingolimod, has been effective in MS. Fingolimod reduces circulating T lymphocytes (including autoreactive ones), protects from neuroinflammation by blocking the effect of S1PR1 expression in astrocytes [24], and helps to regulate the blood-brain barrier [25]. In rats, a positron emission tomography imaging study showed how S1PR1 is upregulated in the lumbar spinal cord of EAE rats and associated with glial cell activation and immune cell infiltration [26]. It has been suggested that fingolimod might exert its action via this dual central-peripheral mechanism [27] and also through modulation of the Treg/Th17 cell balance by regulation of the Akt-mTOR and MAPK/ERK pathways [28].…”

Upregulated Sphingosine 1-Phosphate Receptor 1 Expression in Human and Murine Atherosclerotic Plaques

“…Our group previously reported the radiosynthesis of [ 11 C]TZ3321, which has a nanomolar binding potency and good selectivity for S1PR1 [16]. [ 11 C]TZ3321 has been validated in three rodent models of inflammation: a mouse wire-injury model of neointimal hyperplasia [16], a rat EAE model of multiple sclerosis [32], and a rat carotid injury model of acute vascular inflammation [33]. In the current study, we confirmed the specificity of [ 11 C]TZ3321 by in vitro autoradiography in human femoral plaque tissue and further validated the radioligand in the ApoE −/− mouse model of atherosclerosis for detecting the plaque.…”