Silencing of the RNA-binding protein HuR attenuates hyperalgesia and motor disability in experimental autoimmune encephalomyelitis

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Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system associated with progressive neuronal loss and axonal degeneration. Neuronal lesions and dysfunction lead often to neuropathic pain, the most prevalent and difficult to treat pain syndrome observed in MS patients. Despite its widespread occurrence, the underlying neural mechanisms for MS pain are not fully understood. For a better clarification of the pathophysiology of MS-associated pain, we investigated the role of HuR, an RNA-binding protein that positively regulates the stability of many target mRNAs, including several cytokines. The influence of HuR in the generation of the hypernociceptive response in a mouse model of relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE), an experimental model of MS, was investigated. HuR silencing, obtained through the repeated intrathecal administration of an antisense oligonucleotide (aODN) anti-HuR, completely attenuated hindpaw mechanical allodynia and thermal hyperalgesia developed by RR-EAE mice. Anti-HuR aODN also reduced severity of motor deficits as reflected by a reduction of clinical EAE score and improvement of rotarod performance. RR-EAE mice showed demyelination in spinal cord sections that was significantly reduced by HuR silencing. Double-staining immunofluorescence studies showed a neuronal localization of HuR within dorsal horn spinal cord, consistent with a neuronal mechanism of action. Our findings suggest the involvement of HuR in the hypernociceptive behaviour of RR-EAE mice providing the first pharmacological assessment of an antiallodynic and antihyperalgesic effect of HuR silencing. These data may provide support for HuR modulation as a therapeutic perspective for the management of MS-related neuropathic pain.

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