Bruno P. Meloni

Sir Charles Gairdner Hospital

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Neville W. Knuckey

Queen Elizabeth II Medical Centre

Ryan S. Anderton

The University of Notre Dame Australia

Frank Mastaglia

Perron Institute for Neurological and Translational Science

Jane L. Cross

University of Western Australia

Kym Campbell

University of Western Australia

Adam B. Edwards

Sir Charles Gairdner Hospital

Sherif Boulos

Perron Institute for Neurological and Translational Science

Alan J. Lymbery

Murdoch University

David Blacker

University of Western Australia

Vince W. Clark

University of Western Australia

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University of Western Australia

114

Perron Institute for Neurological and Translational Science

Queen Elizabeth II Medical Centre

Murdoch University

Sir Charles Gairdner Hospital

The University of Notre Dame Australia

Curtin University

Edith Cowan University

Sapienza University of Rome

University of Melbourne

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Is magnesium neuroprotective following global and focal cerebral ischaemia? A review of published studies.

PubMed (2006)

Bruno P. Meloni Huaxu Zhu N. Knuckey

Neuroprotective activity with magnesium associated with animal models of cerebral ischaemia, seizure, perinatal hypoxia/ischaemia, subarachnoid haemorrhage and traumatic brain injury has provided the justification for clinical stroke trials. However, the recent IMAGES stroke clinical trial found magnesium to be largely ineffective. Hence, due to the negative stroke trial outcome, current FAST-MAG trial and our own experience with magnesium in cerebral ischaemia animal models, we thought it prudent to review these preclinical and clinical studies. We reviewed nine studies describing the use of magnesium following global cerebral ischaemia and fourteen following focal cerebral ischaemia. Four global ischaemia and six focal ischaemia studies did not show a significant neuroprotective effect with magnesium. In the majority of positive magnesium studies animal body temperature was not monitored post-ischaemia. Thus the effects of post-ischaemic hypothermia cannot be ruled out as a confounding factor in positive magnesium cerebral ischaemia studies. Moreover, data from our own laboratory indicates that magnesium is only neuroprotective when combined with post-ischaemic hypothermia. These data provide a possible explanation of why the IMAGES trial was largely unsuccessful, as current stroke patient management does not involve hypothermia induction. Future preclinical and clinical cerebral ischaemia trials with magnesium should consider combining treatment with mild hypothermia.

Cerebral ischaemia

Stroke

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The Poly-Arginine Peptide R18D Interferes with the Internalisation of α-Synuclein Pre-Formed Fibrils in STC-1 Enteroendocrine Cells

Biomedicines (2023)

Anastazja M. Gorecki Holly L. Spencer Bruno P. Meloni Ryan S. Anderton

In Parkinson's disease (PD), gut inflammation is hypothesised to contribute to α-synuclein aggregation, but gastrointestinal α-synuclein expression is poorly characterised. Cationic arginine-rich peptides (CARPs) are an emerging therapeutic option that exerts various neuroprotective effects and may target the transmission of protein aggregates. This study aimed to investigate endogenous α-synuclein expression in enteroendocrine STC-1 cells and the potential of the CARP, R18D (18-mer of D-arginine), to prevent internalisation of pre-formed α-synuclein fibrils (PFFs) in enteroendocrine cells in vitro. Through confocal microscopy, the immunoreactivity of full-length α-synuclein and the serine-129 phosphorylated form (pS129) was investigated in STC-1 (mouse enteroendocrine) cells. Thereafter, STC-1 cells were exposed to PFFs tagged with Alexa-Fluor 488 (PFF-488) for 2 and 24 h and R18D-FITC for 10 min. After confirming the uptake of both PFFs and R18D-FITC through fluorescent microscopy, STC-1 cells were pre-treated with R18D (5 or 10 μM) for 10 min prior to 2 h of PFF-488 exposure. Immunoreactivity for endogenous α-synuclein and pS129 was evident in STC-1 cells, with prominent pS129 staining along cytoplasmic processes and in perinuclear areas. STC-1 cells internalised PFFs, confirmed through co-localisation of PFF-488 and human-specific α-synuclein immunoreactivity. R18D-FITC entered STC-1 cells within 10 min and pre-treatment of STC-1 cells with R18D interfered with PFF uptake. The endogenous presence of α-synuclein in enteroendocrine cells, coupled with their rapid uptake of PFFs, demonstrates a potential for pathogenic spread of α-synuclein aggregates in the gut. R18D is a novel therapeutic approach to reduce the intercellular transmission of α-synuclein pathology.

Enteroendocrine cell

Alexa Fluor

10.3390/biomedicines11082089

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Citations (2)

Post-ischemic modest hypothermia (35°C) combined with intravenous magnesium is more effective at reducing CA1 neuronal death than either treatment used alone following global cerebral ischemia in rats

Experimental Neurology (2005)

Hongdong Zhu Bruno P. Meloni Christina Bojarski Michael W. Knuckey Neville W. Knuckey

Brain ischemia

10.1016/j.expneurol.2005.01.022

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Citations (57)

NCX3 knockout mice exhibit increased hippocampal CA1 and CA2 neuronal damage compared to wild-type mice following global cerebral ischemia

Experimental Neurology (2007)

Graham Joseph Jeffs Bruno P. Meloni Sophie Sokolow André Herchuelz Stéphane Schurmans

Knockout mouse

Wild type

Brain ischemia

10.1016/j.expneurol.2007.10.013

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Citations (33)

Comparative Assessment of the Proteolytic Stability and Impact of Poly-Arginine Peptides R18 and R18D on Infarct Growth and Penumbral Tissue Preservation Following Middle Cerebral Artery Occlusion in the Sprague Dawley Rat

Neurochemical Research (2021)

Diego Milani Vince W. Clark Kirk W. Feindel David Blacker Michael Bynevelt

Penumbra

10.1007/s11064-021-03251-y

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Is Cholesterol and Amyloid-β Stress Induced CD147 Expression a Protective Response? Evidence that Extracellular Cyclophilin A Mediated Neuroprotection is Reliant on CD147

Journal of Alzheimer s Disease (2014)

Limbikani J. Kanyenda Giuseppe Verdile Ralph N. Martins Bruno P. Meloni Joanne Chieng

The CD147 protein is a ubiquitous multifunctional membrane receptor. Expression of CD147, which is regulated by sterol carrier protein, reportedly modulates amyloid-β (Aβ), the neurotoxic peptide implicated in neuronal degeneration in Alzheimer's disease (AD). Given that high fat/cholesterol is linked to amyloid deposition in AD, we investigated if cholesterol and/or Aβ can alter CD147 expression in rat cortical neuronal cultures. Water-soluble cholesterol and Aβ42 dose-dependently increased CD147 protein expression, but reduced FL-AβPP protein expression. Cholesterol and Aβ42 treatment also increased lactate dehydrogenase release but to varying degrees. Upregulation of CD147 expression was probably mediated by oxidative stress, as H2O2 (3 μM) also induced CD147 protein expression in neuronal cultures. In light of these findings, we investigated if CD147 induction was cytoprotective, a compensatory response to injury, or alternatively, a cell death signal. To this end, we used recombinant adenovirus to overexpress human CD147 (in SH-SY5Y cells and primary cortical neurons), and pre-treated cultures with or without recombinant cyclophilin A (rCYPA) protein, prior to Aβ42 exposure. We showed that increased CD147 expression protected against Aβ42, only when rCYPA protein was added to neuronal cultures. Together, our findings reveal potentially important relationships between cholesterol loading, CD147 expression, Aβ toxicity, and the putative involvement of CYPA protein in neuroprotection in AD.

Cypa

Cyclophilin

10.3233/jad-131442

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Citations (14)

Poly-arginine-18 peptides do not exacerbate bleeding, or improve functional outcomes following collagenase-induced intracerebral hemorrhage in the rat

PLoS ONE (2019)

Lane J. Liddle Ryan Reinders Samantha M. South David Blacker Neville W. Knuckey

Cationic arginine-rich peptides (CARPs) have demonstrated neuroprotective and/or behavioural efficacy in ischemic and hemorrhagic stroke and traumatic brain injury models. Therefore, in this study we investigated the safety and neuroprotective efficacy of the CARPs poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer R18D given in the acute bleeding phase in an intracerebral hemorrhage (ICH) model.One hundred and fifty-eight male Sprague-Dawley rats received collagenase-induced ICH. Study 1 examined various doses of R18D (30, 100, 300, or 1000 nmol/kg) or R18 (100, 300, 1000 nmol/kg) administered intravenously 30 minutes post-collagenase injection on hemorrhage volume 24 hours after ICH. Study 2 examined R18D (single intravenous dose) or R18 (single intravenous dose, plus 6 daily intraperitoneal doses) at 300 or 1000 nmol/kg commencing 30 minutes post-collagenase injection on behavioural outcomes (Montoya staircase test, and horizontal ladder test) in the chronic post-ICH period. A histological assessment of tissue loss was assessed using a Nissl stain at 28 days after ICH.When administered during ongoing bleeding, neither R18 or R18D exacerbated hematoma volume or worsened functional deficits. Lesion volume assessment at 28 days post-ICH was not reduced by the peptides; however, animals treated with the lower R18D 300 nmol/kg dose, but not with the higher 1000 nmol/kg dose, demonstrated a statistically increased lesion size compared to saline treated animals.Overall, both R18 and R18D appeared to be safe when administered during a period of ongoing bleeding following ICH. Neither peptide appears to have any statistically significant effect in reducing lesion volume or improving functional recovery after ICH. Additional studies are required to further assess dose efficacy and safety in pre-clinical ICH studies.

Nissl body

10.1371/journal.pone.0224870

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Citations (12)

Peptides targeting the mitogen-activated protein kinase pathway (JNK/Jun) fail to reduce infarct volume after permanent MCAO in Sprague Dawley rats

Journal of Experimental Stroke and Translational Medicine (2012)

Cindy Si Kym Rouse Campbell Jane Cross Paul M. Watt Nadia Milech

In this study we have assessed the ability of two TAT-fused peptides PYC36D-TAT and JNKI-1D-TAT (JNKI-1 or XG-102), which respectively inhibit jun proto-oncogene (c-Jun) and c-Jun N-terminal kinase (JNK) activation, to reduce infarct volume and improve functional outcome (adhesive tape removal) following permanent focal cerebral ischemia/pMCAO in Sprague Dawley rats. In addition, PYC36L-TAT fused to an ischemic brain homing peptide (HP-PYC36L-TAT) was also assessed. Prior to animal experiments all PYC36D-TAT, JNKI-1D-TAT and HP-PYC36L-TAT peptide batches were tested in vitro and protected cortical neurons against glutamate excitotoxicity. Rats were treated intravenously in two separate trials. Trial 1 used high peptide doses (PYC36D-TAT: 500, 1000 or 1500 nmol/kg; JNKI-1D-TAT: 500, 1000 or 1500 nmol/kg; PYC36Dscrambled-TAT: 1120 nmol/kg) administered 1 hour after MCAO. Trial 2 used lower doses (PYC36D-TAT: 50 or 250 nmol/kg; HP-PYC36L-TAT: 250 nmol/kg; JNKI-1D-TAT: 250 nmol/kg; D-TAT: 250 nmol/kg) administered 2 hours after MCAO. Contrary to other stroke animal studies, but in line with our previous findings, no treatment significantly reduced infarct volume or improved functional score measurements compared to vehicle (saline) treated animals when assessed 24 hours post-MCAO.

Excitotoxicity

10.4172/1939-067x.1000138

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Citations (0)

Brain Sciences Special Issue: Neuroprotection against Ischemic Brain Injury

Brain Sciences (2013)

Bruno P. Meloni

It was my great pleasure to have acted as the guest editor for the Brain Sciences Special Issue on Neuroprotection against Ischemic Brain Injury. This Special Issue consists of a total of 18 articles covering a range of topics with the purpose of providing new knowledge and exploring novel interventions that one day may be used to better protect and repair the brain after ischemia. [...]

Brain ischemia

10.3390/brainsci3031415

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Evaluation of preconditioning treatments to protect near-pure cortical neuronal cultures from in vitro ischemia induced acute and delayed neuronal death

Brain Research (2002)

Bruno P. Meloni Bernadette T. Majda Neville W. Knuckey

Ischemic Preconditioning

Hypoxia

10.1016/s0006-8993(01)03361-3

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Citations (35)