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Multiple sclerosis (MS) is characterized by inflammatory demyelination, astrogliosis and axonal loss in the CNS. Approximately 10-15% of MS patients are diagnosed with primary progressive multiple sclerosis (PPMS), which is characterized by unremitting disease progression from disease onset. We have previously reported that intrathecal delivery of PPMS cerebrospinal fluid (CSF) induces motor deficits and spinal cord pathology in mice. Here, we investigated whether filtration of PPMS CSF would remove pathology-inducing factors and improve functional outcome in mice.
A tangential flow filtration (TFF) system was used to pass PPMS CSF through 5kDa hollow-fiber filters. Following 3 filtration cycles, CSF protein concentration was significantly reduced, as measured by BCA assay. 8-10 week old female mice underwent laminectomies at cervical levels 4 and 5, and either PPMS CSF or filtered PPMS CSF was injected under the dura mater into the subarachnoid space. Control animals were injected with saline. All motor testing and histological analyses were performed in a blinded manner. Functional deficits were assessed by evaluating forelimb grip strength, reaching accuracy and tail rigidity at 1 day following intrathecal CSF delivery. Mice injected with PPMS CSF displayed significantly higher motor deficit scores and weaker grip strength than mice injected with filtered PPMS CSF and saline controls. Mice were perfused at 1 day post injection (DPI). Spinal cords were post-fixed overnight in 4% paraformaldehyde, cryoprotected in 30% sucrose, then cryosectioned for histological analyses. In cervical spinal cords of PPMS CSF-injected mice, demyelinated lesions were observed, as revealed by luxol fast blue staining. At 1DPI, evidence of reactive astrogliosis and axonal damage was also observed, as revealed by significantly stronger GFAP and SMI-32 immunostaining intensities, respectively. None of these pathological changes were observed in mice injected with filtered PPMS CSF, or control mice. These data provide preclinical support for the testing of NeurapheresisTM Therapy in PPMS patients.
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