Oxidative Status in Multiple Sclerosis and Off-Targets of Antioxidants: The Case of Edaravone.

BACKGROUND: MS is a chronic inflammatory disease of the CNS leading to demyelination and neurodegeneration, with a complex and still to be clarified aetiology. Several data, coming from patients' samples and from animal models, show that Oxidative Status (OS) plays an important role in MS pathogenesis. Overproduction of reactive oxidative species by macrophages/microglia can bring about cellular injury and ensuing cell death by oxidizing cardinal cellular components. Oxidized molecules are present in active MS lesions and are associated with neurodegeneration. METHODS: We undertook a structured search of bibliographic databases for peer-reviewed research literature focusing on OS in MS. The contents of the selected papers were described in the context of a conceptual framework. A special emphasis was given to the results of our study in the field. RESULTS: The results of our three recent studies were put in the context and discussed taking into account the literature on the topic. Oxidative damage underpinned an imbalance shared by MS and neurodegenerative diseases such as Alzheimer and Parkinson diseases. In people with clinically isolated syndrome (an early phase of MS) oxidative stress proved to contribute to disease pathophysiology and to provide biomarkers that may help predict disease evolution. A drug screening platform based on multiple assays to test the remyelinating potential of library of approved compounds showed two anti-oxidants, edaravone and 5-methyl-7- methoxyisoflavone, as active drugs. Moreover, an analysis of 'structure activity relationship' showed off-targets sites of these compounds that accounted for their remyelinating activity, irrespective of their antioxidant action. CONCLUSION: Overall, edaravone emerges as a candidate to treat complex disease such as MS, where inflammation, oxidative stress and neurodegeneration contribute to disease progression, together or individually, in different phases and disease types. Furthermore, approaches based on drug repositioning seem to maintain the promise of helping discover novel treatment for complex diseases, where molecular targets are largely unknown.

Effects of age-related loss of P/Q-type calcium channels in a mice model of peripheral nerve injury.

We analyzed the role of P/Q-type calcium channels in sciatic nerve regeneration after lesion induced by chronic constriction injury (CCI) in heterozygous null mutant mice lacking the CaV2.1α1 subunit of these channels (Cacna1a+/-). Compared with wild type, Cacna1a+/- mice showed an initial reduction of the CCI-induced allodynia, indicating a reduced pain perception, but they also evidenced a lack of recovery over time, with atrophy of the injured hindpaw still present 3 months after CCI when wild-type mice fully recovered. In parallel, Cacna1a+/- mice exhibited an early onset of age-dependent loss of P/Q-type channels, which can be responsible for the lack of functional recovery. Moreover, Cacna1a+/- mice showed an early age-dependent reduction of muscular strength, as well as of Schwann cells proliferation and sciatic nerve remyelination. This study demonstrates the important role played by P/Q-type channels in recovery from nerve injury and has important implications for the knowledge of age-related processes.

Botulinum neurotoxin A enhances the analgesic effects on inflammatory pain and antagonizes tolerance induced by morphine in mice.

Over the recent years compelling evidence has accumulated indicating that botulinum neurotoxin serotype A (BoNT/A) results in analgesic effects on neuropathic as well as inflammatory pain, both in humans and in animal models. In the present study, the pharmacological interaction of BoNT/A with morphine in fighting inflammatory pain was investigated in mice using the formalin test. Moreover, the effects of BoNT/A on the tolerance-induced by chronic administration of morphine were tested and the behavioral effects were correlated with immunofluorescence staining of glial fibrillary acidic protein, the specific marker of astrocytes, at the spinal cord level. An ineffective dose of BoNT/A (2 pg/paw) combined with an ineffective dose of morphine (1 mg/kg) exerted a significant analgesic action both during the early and the late phases of formalin test. A single intraplantar injection of BoNT/A (15 pg/paw; i.pl.), administered the day before the beginning of chronic morphine treatment (7 days of s.c. injections of 20 mg/kg), was able to counteract the occurrence of tolerance to morphine. Moreover, BoNT/A reduces the enhancement of the expression of astrocytes induced by inflammatory formalin pain. Side effects of opiates, including the development of tolerance during repeated use, may limit their therapeutic use, the possibility of using BoNT/A for lowering the effective dose of morphine and preventing the development of opioid tolerance would have relevant implications in terms of potential therapeutic perspectives.