Contributions
Abstract: 136
Type: Oral
Increasing observations favour an important role for mitochondrial dysfunction and energy deficits in the pathophysiology of MS, and here we provide evidence that they can cause both loss of function, and, separately, demyelination, two of the cardinal features of MS. We report roles for reduced blood flow, tissue hypoxia, and mitochondrial dysfunction.
At the onset of EAE, mitochondria in mouse spinal cord axons are depolarised (incapable of making ATP) and fragmented, with impaired trafficking, and these deficits parallel the expression of neurological deficit, reversing during remission and reoccurring during relapse. The mitochondrial dysfunction is accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial respiratory chain complex I activity. The dysfunction is most severe in regions containing perivascular inflammatory cells, but it precedes any demyelination or axonal degeneration, indicating that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.
At disease onset, the mitochondrial dysfunction occurs in conjunction with severe tissue hypoxia, and we have found that the hypoxia is spatially, temporally and quantitatively correlated with the magnitude of neurological deficits. We report that hypoxia is also associated with the pathogenesis of experimental demyelination of the Pattern III subtype found in MS. Indeed, demyelinating lesions in MS occur preferentially in vascular watershed regions, where perfusion is most vulnerable.
The changing expression of neurological deficits in EAE is matched by reductions in spinal grey matter blood flow, as revealed by our novel MRI protocol. The reduced flow causes at least some of the mitochondrial dysfunction because increasing inspired oxygen improves spinal mitochondrial function as assessed by near infrared spectroscopy. We also report that increased oxygen administration improves neurological deficits and reduces demyelination in EAE and in experimental Pattern III lesions.
We conclude that reduced vascular perfusion of the inflamed CNS causes tissue hypoxia and mitochondrial dysfunction resulting in neurological deficits and demyelination. Notably, breathing increased oxygen can alleviate the deficits and demyelination. If safety is established, oxygen may be an effective therapy for inflamed CNS tissue.
Disclosure: KJS has received project funding from Biogen, Genzyme, MerckSerono, MRC, MS Society UK, National MS Society USA, Rosetrees Trust, UCB, & Wellcome Trust.
AD has nothing to disclose.
RD has nothing to disclose.
MSad has nothing to disclose.
MA has nothing to disclose.
MT has nothing to disclose.
PK has nothing to disclose.
DS is funded by UCL.
MSaj has received consultancy fees from UCB.
IH has nothing to disclose.
NX has nothing to disclose.
SH has nothing to disclose.
MK has nothing to disclose.
RD has received grants from the German Research Foundation, the Hertie Foundation and the Federal Ministry for Education and Research.
IT is funded by EPSRC, MRC, ERC & Wellcome Trust.
XG has received project funding from Chiesi Pharmaceutical, and is the current CEO of Gold Standard Phantoms Ltd.
MD has nothing to disclose.
Abstract: 136
Type: Oral
Increasing observations favour an important role for mitochondrial dysfunction and energy deficits in the pathophysiology of MS, and here we provide evidence that they can cause both loss of function, and, separately, demyelination, two of the cardinal features of MS. We report roles for reduced blood flow, tissue hypoxia, and mitochondrial dysfunction.
At the onset of EAE, mitochondria in mouse spinal cord axons are depolarised (incapable of making ATP) and fragmented, with impaired trafficking, and these deficits parallel the expression of neurological deficit, reversing during remission and reoccurring during relapse. The mitochondrial dysfunction is accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial respiratory chain complex I activity. The dysfunction is most severe in regions containing perivascular inflammatory cells, but it precedes any demyelination or axonal degeneration, indicating that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS.
At disease onset, the mitochondrial dysfunction occurs in conjunction with severe tissue hypoxia, and we have found that the hypoxia is spatially, temporally and quantitatively correlated with the magnitude of neurological deficits. We report that hypoxia is also associated with the pathogenesis of experimental demyelination of the Pattern III subtype found in MS. Indeed, demyelinating lesions in MS occur preferentially in vascular watershed regions, where perfusion is most vulnerable.
The changing expression of neurological deficits in EAE is matched by reductions in spinal grey matter blood flow, as revealed by our novel MRI protocol. The reduced flow causes at least some of the mitochondrial dysfunction because increasing inspired oxygen improves spinal mitochondrial function as assessed by near infrared spectroscopy. We also report that increased oxygen administration improves neurological deficits and reduces demyelination in EAE and in experimental Pattern III lesions.
We conclude that reduced vascular perfusion of the inflamed CNS causes tissue hypoxia and mitochondrial dysfunction resulting in neurological deficits and demyelination. Notably, breathing increased oxygen can alleviate the deficits and demyelination. If safety is established, oxygen may be an effective therapy for inflamed CNS tissue.
Disclosure: KJS has received project funding from Biogen, Genzyme, MerckSerono, MRC, MS Society UK, National MS Society USA, Rosetrees Trust, UCB, & Wellcome Trust.
AD has nothing to disclose.
RD has nothing to disclose.
MSad has nothing to disclose.
MA has nothing to disclose.
MT has nothing to disclose.
PK has nothing to disclose.
DS is funded by UCL.
MSaj has received consultancy fees from UCB.
IH has nothing to disclose.
NX has nothing to disclose.
SH has nothing to disclose.
MK has nothing to disclose.
RD has received grants from the German Research Foundation, the Hertie Foundation and the Federal Ministry for Education and Research.
IT is funded by EPSRC, MRC, ERC & Wellcome Trust.
XG has received project funding from Chiesi Pharmaceutical, and is the current CEO of Gold Standard Phantoms Ltd.
MD has nothing to disclose.