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The Perron Institute’s Molecular Neurobiology Research Includes Stroke Research.

Stroke Research

The objective of the Perron Institute’s Stroke Research led by Adjunct Associate Professor Bruno Meloni and Clinical Professor Neville Knuckey is to develop treatments to minimise brain damage after stroke and cerebral ischaemia.

Researchers have discovered that peptides rich in the amino acid arginine are highly neuroprotective and can limit brain damage after a stroke.

Stroke is Australia’s second biggest killer after coronary heart disease and a leading cause of disability. One in six people will suffer from a stroke during their lifetime with over 400,000 Australians currently living with the debilitating aftereffects of the disorder. By 2032, it is estimated that over 700,000 Australian will be living with the effects of stroke.

Stroke Research Focus

At present, available treatments are not satisfactory. To this end, the Stroke Research Group have been:

i) identifying and characterising potential neuroprotective proteins

ii) assessing the potential of the sodium calcium exchanger (NCX) membrane ion transporter to protect neurons from ischaemia;

iii) assessing the efficacy of mild hypothermia when used with magnesium and other putative neuroprotective agents/treatments; and

iv) assessing the potential of arginine-rich peptides as neuroprotective agents.

Perron Institute | Stroke Research

Associate Professor Bruno Meloni

Stroke Research Members

Stroke Research Team Achievements

GRANTS

Pre-clinical assessment of poly-arginine peptides in stroke. Meloni and Knuckey. 2016: Stage 2: $65,000. Pathfinder, University of WA.

Pre-clinical assessment of the neuroprotective efficacy of arginine-rich peptides in neurotrauma injury models. Meloni/Knuckey/Hodgetts/Cross. 2016: $113,636. Neurotrauma Research Program of WA.

Dr Jane Cross, A/Prof Bruno Meloni, Clp Neville Knuckey, Dr David Blacker 2015, ‘Pre-clinical Assessment of Poly-arginine Peptides as a Treatment to Reduce Brain Damage Following Stroke’, National Stroke Foundation.

A/Prof Bruno Meloni, Clp Neville Knuckey, Ms Li Chiu, Dr Jane Cross, Mr Vince Clark 2015-16, ‘Pre-clinical assessment of arginine-rich peptides as a treatment to reduce brain damage following traumatic brain injury’, Brain Foundation.

PUBLICATIONS

2018 Publications

  • Edwards AB, Anderton RS, Knuckey NW, Meloni BP. (2018). Assessment of therapeutic window for poly-arginine-18D (R18D) in a P7 rat model of perinatal hypoxic-ischaemic encephalopathy. Journal of Neuroscience Research. In press.
  • Edwards AB, Anderton RS, Knuckey NW, Meloni BP. (2018). Review: Perinatal hypoxic-ischaemic encephalopathy and neuroprotective peptide therapies: a case for cationic arginine-rich peptides (CARPs). Brain Sciences. In press.
  • Milani D, Bakeberg MC, Cross JL, Clark VW, Anderton, RS, Blacker DJ, Knuckey NW, Meloni BP (2018).  Comparison of neuroprotective efficacy of poly-arginine R18 and R18D (D-enantiomer) peptides following permanent middle cerebral artery occlusion in the Wistar rat and in vitro toxicity studies. PlosOne 13(3): e0193884. https://doi.org/10.1371/journal.pone.0193884
  • Adam B. Edwards, Jane L. Cross, Ryan S. Anderton, Neville W. Knuckey and Bruno P. Meloni (2018). Poly-arginine R18 and R18D (D-enantiomer) peptides reduce infarct volume and improves behavioural outcomes following perinatal hypoxic-ischaemic encephalopathy in the P7 rat. Molecular Brain (2018) 11:8. doi.org/10.1186/s13041-018-0352-0

2017 Publications

  • Assessment of R18, COG1410, and APP96-110 in excitotoxicity and traumatic brain injury. Chiu LS, Anderton RS, Clark VW, Edwards AB, Knuckey NW, Meloni BP. (2017). Translational Neuroscience. DOI: https://doi.org/10.1515/tnsci-2017-0021
  • Delayed 2h post-stroke administration of R18 and NA-1 (TAT-NR2B9c) peptides after permanent and/or transient middle cerebral artery occlusion in the rat. Milani, D, Cross, JL. Anderton, RS, Blacker, DJ, Knuckey, NW, Meloni, BP. (2017). Brain Research Bulletin 28, 135:62-68. DOI: 10.1016/j.brainresbull.2017.09.012
  • Neuroprotective efficacy of R18 poly-arginine and NA-1 (TAT-NR2B9c) peptides following transient middle cerebral artery occlusion in the rat. Milani, D, Cross, JL, Anderton, RS, Blacker, DJ, Knuckey, NW, Meloni, BP. 2017 Neuroscience Research 114:9-15

  • Characterisation of neuroprotective efficacy of modified poly-arginine-9 (R9) peptides in neuronal glutamic acid excitotoxicity model. Edwards AB, Cross JL, Anderton RS, Knuckey NW, Meloni BP. 2017 Mol Cell Biochem 426:75-85
  • The neuroprotective peptide poly-arginine-12 (R12) reduces cell surface levels of NMDA NR2B receptor subunit in cortical neurons; investigation into the involvement of endocytic mechanisms. MacDougall G, Anderton RS, Edwards AB, Knuckey NW, Meloni BP. 2017 Journal of Molecular Neuroscience 61:235-246
  • Peptide pharmacological approaches to treating traumatic brain injury: a case for arginine-rich peptides. Chiu LS, Anderton RS, Knuckey NW, Meloni BP. 2017 Molecular Neurobiology. DOI 10.1007/s12035-016-0287-3
  • Assessment of the neuroprotective effects of arginine-rich protamine peptides, poly-arginine peptides (R12-cylic, R22) and arginine-tryptophan containing peptides following in vitro excitotoxicity and/or permanent middle cerebral artery occlusion in rats
    Meloni BP, Milani D, Cross JL, Clark VW, Edwards AB, Anderton RS, Blacker DJ, Knuckey NW. 2017 Neuromolecular Medicine 19: 271-285
  • Modification to the Rice-Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48 hours. Edwards AB, Feindel KW, Cross JL, Anderton RS, Clark VW, Knuckey NW, Meloni BP
    2017 Journal of Neuroscience Methods 288:62-71
  • Delayed 2-hour post-stroke administration of R18 and NA-1 (TAT-NR2B9c) peptides after permanent and/or transient middle cerebral artery occlusion in the rat. Milani D, Cross JL, Anderton RS, Blacker DJ, Knuckey NW, Meloni BP. 2017 Brain Research Bulletin 135:62-68
  • Assessment of R18, COG1410, and APP96-110 in excitotoxicity and traumatic brain injury. Chiu LS, Anderton RS, Cross JL, Clark VW, Edwards AB, Knuckey NW, Meloni BP. 2017 Translational Neuroscience 15; 8:147-157
  • Pathophysiology and Neuroprotective Strategies in Hypoxic-Ischemic. Brain Injury and Stroke. Meloni BP. 2017 Editorial, Brain Sciences 7, 110; doi:10.3390/brainsci7080110

2016 Publications

  • Characterisation of neuroprotective efficacy of modified poly-arginine-9 (R9) peptides in neuronal glutamic acid excitotoxicity model. Edwards AB, Cross JL, Anderton RS, Knuckey NW, Meloni BP.  (2016). Mol Cell Biochem DOI 10.1007/s11010-016-2882-z.
  • The neuroprotective potential of arginine-rich peptides for the acute treatment of traumatic brain injury. Chiu LS, Anderton RS, Knuckey NW, Meloni BP.  (2016). Expert Review of Neurotherapeutics. 16(4):361-363.
  • Peptide pharmacological approaches to treating traumatic brain injury: a case for arginine-rich peptides. Chiu LS, Anderton RS, Knuckey NW, Meloni BP. Molecular Neurobiology. DOI 10.1007/s12035-016-0287-3.

  • Poly-arginine peptides reduce infarct volume in a permanent middle cerebral artery rat stroke model
    Diego Milani; Bruno Meloni; Vince Clark; Jane Cross; Ryan Anderton; Neville Knuckey (2016)
    BMC Neurosci, 17(1), 19. doi: 10.1186/s12868-016-0253-z.
  • The R18 poly-arginine peptide is more effective than the TAT-NR2B9c (NA-1) peptide when administered 60 minutes after permanent middle cerebral artery occlusion in the rat. Diego Milani, Neville Knuckey, Ryan Anderton, Jane Cross and Bruno Meloni. (2016)
    Stroke Res Treat, 2016, 2372710. doi: 10.1155/2016/2372710.
  • Bird, S.M., Sohrabi, H.R., Sutton, T.A., Weinborn, M., Rainey-Smith, S.R., Brown, B., Patterson, L., Taddei, K., Gupta, V., Carruthers, M., Lenzo, N., Knuckey, N., Bucks, R.S., Verdile, G., Martins, R.N. (2016) ‘Cerebral amyloid-β accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies’, Neuroscience and Biobehavioral Reviews, 64, 1, pp. 215-228. Detail

2015 Publications

  • Meloni, B.P. & Knuckey, N.W. (2015) Magnesium may provide further benefit to hypothermia following perinatal asphyxia encephalopathy, Journal of Perinatal Medicine, 43 (1), pp. 125-126.
  • Meloni, B.P., Brookes, L.M., Clark, V.W., Cross, J.L., Edwards, A.B., Anderton, R.S., Hopkins, R.M., Hoffmann, K. & Knuckey, N.W. (2015) Poly-arginine and arginine-rich peptides are neuroprotective in stroke models, Journal of Cerebral Blood Flow and Metabolism, 35 (6) pp. 993-1004.
  • Meloni, B.P., Milani D., Adam B. Edwards A.B., Anderton, R.S., O’Hare Doig, R.L., Fitzgerald M., Palmer T.N., Knuckey, N.W. (2015). Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties. Pharmacology and Therapeutics. In press.
  • Meloni BP, Craig AJ, Milech N, Hopkins RM, Watt PM, Knuckey NW. (2014). The Neuroprotective Efficacy of Cell-Penetrating Peptides TAT, Penetratin, Arg-9, and Pep-1 in Glutamic Acid, Kainic Acid, and In Vitro Ischemia Injury Models Using Primary Cortical Neuronal Cultures. Cell Mol Neurobiol 2014;34:173-181
  • Teoh J, Boulos S, Chieng J,  W. Knuckey NW, Meloni BP. (2014). Erythropoietin increases neuronal NDPKA expression, and NDPKA up-regulation as well as exogenous application protects cortical neurons from in vitro ischemia-related insults. Cellular and Molecular Neurobiology.  DOI 10.1007/s10571-013-0023-8.
  • Teoh J, Boulos S, Chieng J, Knuckey NW, Meloni BP. (2014). Over-expressing prohibitin (PHB) in neuronal cultures exacerbates cell death following hydrogen peroxide and l-glutamic acid induced injury.  Neuroscience and Medicine 5: 149-160.
  • Anderton RS, Meloni BP, Mastaglia FL, Boulos S. (2014). Investigation of a recombinant SMN protein delivery system to treat spinal muscular atrophy. Translational Neuroscience. 2014; 5(1):8-16.
  • Greene ID, Mastaglia F, Meloni BP, West KA, Chieng J, Mitchell CJ, Gai WP, Boulos S.  (2014).Evidence that the LRRK2 ROC domain Parkinson’s disease-associated mutants A1442P and R1441C exhibit increased intracellular degradation.  J Neuroscience Research 2014; 92(4):506-516.
  • Kanyenda LJ, Verdile G, Martins RN, Meloni BP, Chieng, J, Mastaglia FL, Laws SM, Anderton RS, Boulos, S. (2014). Is cholesterol and Aβ stress induced CD147 expression a protective response?: evidence that extracellular cyclophilin A mediated neuroprotection is reliant on CD147. Journal of Alzheimer’s Disease 39, 545–556.
  • Meloni BP and Knuckey NW (2014). Magnesium may provide further benefit to hypothermia following perinatal asphyxia encephalopathy. Journal of Perinatal Medicine, 43, 125-126. Letter to the Editor.
  • Meloni, B.P., Cross J.L., Brookes, L.M., Clark V.W., Campbell, K., Knuckey, N.W. (2013). Using FAST-Mag Protocol With Or Without Mild Hypothermia (35°C) Does Not Improve Outcome After Permanent MCAO In Rats. Magnesium Research, 26 (2): 67-73.
  • Cross, J.L., Boulos, B., Shepherd, K.L., Craig, A.J., Lee, S., Bakker, A.J., Knuckey, N.W, Meloni, B.P. (2012). High level over-expression of different NCX isoforms in HEK293 cells and primary neuronal cultures is protective following oxygen glucose deprivation, Neuroscience Research 73(3): 191-198.
  • Meloni, B.P., Meade, A.J., Kitikomolsuk, D., Knuckey, N.W. (2011). Characterisation of neuronal cell death in acute and delayed in vitro ischaemia (oxygen/glucose deprivation) models. Journal of Neuroscience Methods. 195: 67-74.