Neurologic and Histologic Tests Used to Measure Neuroprotective Effectiveness of Virus-Derived Immune-Modulating Protein
Severe inflammatory disease initiated by neurotrauma and stroke is of primary concern in these intractable pathologies as noted in recent studies and understanding of the pathogenesis of spinal cord injury (SCI) in the rat model. Successful anti-inflammat
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Introduction Spinal cord injury (SCI) causes local hemorrhages, massive necrosis, and edema leading to severe, macrophage-rich inflammation starting at day 3 that lasts for over 16 weeks and considerably adds to destruction of the spinal cord [1]. Immunomodulatory proteins
Alexandra R. Lucas (ed.), Viruses as Therapeutics: Methods and Protocols, Methods in Molecular Biology, vol. 2225, https://doi.org/10.1007/978-1-0716-1012-1_13, © Springer Science+Business Media, LLC, part of Springer Nature 2021
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derived from myxoma virus, Serp-1 and M-T7 [2, 3], have been shown to have a potent anti-inflammatory therapeutic effect on animal models of vasculitis [4], organ transplant [5], and spinal cord injury (SCI) ( [6, 7], see Note 1). Continuous subdural infusion of 0.2 mg/rat of Serp-1 or M-T7 from an Alzet 2ML1 osmotic pump for 7 days resulted in improvement in hind-end (HE) locomotor test and toe-pinch withdrawal test and in a 50–80% reduction of macrophage infiltration in the cavity of injury (COI) considered as a neuroprotective effect ( [6], see Note 1). Intraperitoneal infusion of either protein from the 2ML1 osmotic pump resulted in no (for Serp-1) or little (for M-T7) effect [6], indicating that a systemic administration of both proteins is not effective in the neuroprotective treatment of SCI and that a continuous intralesional delivery is required. In a more recent experiment, a chitosan hydrogel loaded with Serp-1 was implanted into the dorsal spinal column crush [8] to determine whether the intralesional delivery would result in neuroprotection. 100 μg of Serp-1 in 50 μL of hydrogel injected into the crush lesion was associated with better initial neurological recovery on both HE locomotor and toe-pinch withdrawal tests and also with reduction of the size of the crush lesion within 28 days of the study indicating an early neuroprotective effect (see Note 2). The intralesional implant of a hydrogel loaded with an anti-inflammatory compound may potentially lead to secondgeneration treatments of the SCI where neuroprotective effect of the drug released from the hydrogel is combined with the function of the hydrogel to act as a bridge for axonal regeneration across the SCI [8]. In a previous study, the implantation of choroid plexus cells into the acute spinal crush lesion in the dysmyelinated LongEvans shaker (LES) rat resulted in exogenous ependymal cells guiding regenerating axons across the COI, their support, and integration into the peri-lesional white matter [9] indicating that such a therapeutic strategy is feasible. The studies using subdural infusion or intra-lesional implantation of viral immunomodulatory proteins as anti-inflammatory/ neuroprotective agents in SCI [6, 7] offered an opportunity to develop simplified and improved neurological tests to measure the success of a neuroprotective treatment and also to understand their limitations (see Note 3). While a BBB locomotor test, established by Basso, Beatie, Bresnahan et al. [10], has been widely used as a fund
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