Title : LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats
Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have emerged as having potential neuroprotective and neuroregenerative properties. We investigated the effect of intranasal administration of LINGO-1–directed siRNA-loaded chitosan nanoparticles on demyelination and remyelination processes in a rat model of demyelination. Adult male Wistar rats were randomly assigned to one of 6 groups (n = 10 each) and subjected to intrapontine stereotaxic injection of ethidium bromide (EB) to induce demyelination. EB-treated rats were either left untreated or received intranasal LINGO-1–directed siRNA–chitosan nanoparticles from day 1 to day 7 (demyelination group) or from day 7 to day 21 (remyelination group) after EB injection. Chitosan nanoparticle (50 μl) was given alone after EB stereotaxic injection for both demyelination and remyelination groups. Two additional groups received 10 μl of saline by stereotaxic injection, followed by intranasal saline as controls for demyelination and remyelination groups (n = 10/group). Behavioural testing was conducted for all rats, as well as terminal biochemical assays and pathological examination of pontine tissues were done. After EB injection, rats had compromised motor performance and coordination. Pathological evidence of demyelination was observed in pontine tissue and higher levels of caspase-3 activity were detected compared to control rats. With LINGO-1–directed siRNA–chitosan nanoparticle treatment, animals performed better than controls. Remyelination-treated group showed better motor performance than demyelination group. LINGO-1 downregulation was associated with signs of repair in histopathological sections, higher expression of pontine myelin basic protein (MBP) mRNA and protein and lower levels of caspase-3 activity indicating neuroprotection and remyelination enhancement.
Audience Take Away:
• Efficient delivery of small interfering RNAs (siRNAs) remains a challenge and much research has been aimed at developing ideal gene delivery carriers.
• RNA interference is a new strategy to block LINGO-1expression in the target lesions with low doses and less systemic side effects.
• Chitosan nanoparticles have become one of the most studied polymers in non-viral siRNA delivery, due to their polycationic nature and biocompatibility.
• LINGO-1–directed siRNA loaded chitosan nanoparticles can improve neurological, neurochemical disturbance and enhance remyelination in demyelination rat model.
• Intranasal route of LINGO-1–directed siRNA nanoparticles administration appears to be an effective tool for drug delivery to bypass the BBB and directly deliver drugs to the CNS.