Neuroprotection by safinamide in the 6-hydroxydopamine model of Parkinson's disease

AIMS: Current therapies in Parkinson's disease mainly treat symptoms rather than provide effective neuroprotection. We examined the effects of safinamide (monoamine oxidase B and sodium channel blocker) on microglial activation and the degeneration of dopaminergic neurons in a rat model of PD in vivo, and on microglia in vitro. METHODS: Rats received unilateral stereotaxic injection of 6-hydroxydopamine into the medial forebrain bundle on day 0: The contralateral side served as control. Safinamide or vehicle was delivered from days 0 or 1, for 7 days, via sub-cutaneous mini-pumps. RESULTS: In vehicle-treated rats 6-hydroxydopamine caused a significant increase in the number of activated MHC-II(+) microglia compared with the contralateral side, and only 50% of the dopaminergic neurons survived in the ipsilateral SNc. In contrast, rats treated daily with safinamide 50 and 150 mg/ml (on day 0 or 1) exhibited a significantly reduced number of activated microglia (55% reduction at 150 mg/ml) and a significant protection of dopaminergic neurons (80% of neurons survived) (P < 0.001) compared with vehicle-treated controls. Rasagiline, a monoamine oxidase B inhibitor, and lamotrigine, a sodium channel blocking drug, also protected dopaminergic neurons, indicating that safinamide may act by either or both mechanisms. Safinamide also reduced the activation of microglial cells in response to lipopolysaccharide exposure in vitro. CONCLUSION: Safinamide therapy suppresses microglial activation and protects dopaminergic neurons from degeneration in the 6-hydroxydopamine model of PD, suggesting that the drug not only treats symptoms but also provides neuroprotection

Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis

Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiplesclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS