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In JoVE (1)
- Performing Permanent Distal Middle Cerebral with Common Carotid Artery Occlusion in Aged Rats to Study Cortical Ischemia with Sustained Disability
Other Publications (3)
Articles by Denise A. Duricki in JoVE
Performing Permanent Distal Middle Cerebral with Common Carotid Artery Occlusion in Aged Rats to Study Cortical Ischemia with Sustained Disability
Christina Wayman*1,2, Denise A. Duricki*1,2, Lisa A. Roy3, Barbara Haenzi1, Shi-Yen Tsai4, Gwendolyn Kartje4,5,6, John S. Beech7, Diana Cash2, Lawrence Moon1
1Wolfson Centre for Age-Related Diseases, King's College London, University of London, 2Department of Neuroimaging, James Black Centre, Institute of Psychiatry, King's College London, University of London, 3Institute of Neuroscience and Psychology, Wellcome Surgical Institute, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, 4Research Service, Edward Hines Jr. VA Hospital, 5Neurology Service, Edward Hines Jr. VA Hospital, 6Department of Molecular Pharmacology and Therapeutics, Neuroscience Research Institute, Loyola University Chicago, 7Department of Oncology, The Gray Institute for Radiation, Oncology and Biology, University of Oxford
Other articles by Denise A. Duricki on PubMed
Delayed Treatment with Chondroitinase ABC Promotes Sensorimotor Recovery and Plasticity After Stroke in Aged Rats
Brain : a Journal of Neurology. Apr, 2012 | Pubmed ID: 22396394
Stroke is the dominant cause of sensorimotor disability that primarily affects the elderly. We now show that neuroplasticity and functional recovery after stroke is constrained by inhibitory chondroitin sulphates. In two blinded, randomized preclinical trials, degradation of chondroitin sulphate using chondroitinase ABC reactivated neuroplasticity and promoted sensorimotor recovery after stroke in elderly rats. Three days after stroke, chondroitinase ABC was microinjected into the cervical spinal cord to induce localized plasticity of forelimb sensorimotor spinal circuitry. Chondroitinase ABC effectively removed chondroitin sulphate from the extracellular matrix and perineuronal nets. Three different tests of sensorimotor function showed that chondroitinase ABC promoted recovery of forelimb function. Anterograde and retrograde tracing showed that chondroitinase ABC also induced sprouting of the contralesional corticospinal tract in the aged treated hemicord. Chondroitinase ABC did not neuroprotect the peri-infarct region. We show for the first time delayed chondroitinase ABC treatment promotes neuroanatomical and functional recovery after focal ischaemic stroke in an elderly nervous system.
Neuropharmacology. Feb, 2014 | Pubmed ID: 24055502
Pasteurella multocida toxin (PMT) activates the G-proteins Gαi(₁₋₃), Gα(q), Gα₁₁, Gα₁₂ and Gα₁₃ by deamidation of specific glutamine residues. A number of these alpha subunits have signalling roles in neurones. Hence we studied the action of this toxin on rat superior cervical ganglion (SCG) neurones and NG108-15 neuronal cells. Both Gα(q) and Gα₁₁ could be identified in SCGs with immunocytochemistry. PMT had no direct action on Kv7 or Cav2 channels in SCGs. However PMT treatment enhanced muscarinic receptor mediated inhibition of M-current (Kv7.2 + 7. 3) as measured by a 19-fold leftward shift in the oxotremorine-M concentration-inhibition curve. Agonists of other receptors, such as bradykinin or angiotensin, that inhibit M-current did not produce this effect. However the amount of PIP₂ hydrolysis could be enhanced by PMT for all three agonists. In a transduction system in SCGs that is unlikely to be affected by PMT, Go mediated inhibition of calcium current, PMT was ineffective whereas the response was blocked by pertussis toxin as expected. M1 muscarinic receptor evoked calcium mobilisation in transformed NG108-15 cells was enhanced by PMT. The calcium rises evoked by uridine triphosphate acting on endogenous P2Y₂ receptors in NG108-15 cells were enhanced by PMT. The time and concentration dependence of the PMT effect was different for the resting calcium compared to the calcium rise produced by activation of P2Y₂ receptors. PMT's action on these neuronal cells would suggest that if it got into the brain, symptoms of a hyperexcitable nature would be seen, such as seizures.
Brain : a Journal of Neurology. Jan, 2016 | Pubmed ID: 26614754
There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.