Following the first report of avian Giardia infection in Australia, isolates of the parasite recovered from naturally infected straw-necked ibis (Theskiornis spinicollis) were characterized using median body morphology, scanning electron microscopy, multilocus enzyme electrophoresis, random amplified polymorphic DNA (RAPD), and small subunit ribosomal RNA (SSU-rRNA) analyses. Results were compared with Giardia from other birds and mammals, and the extent of genetic diversity between a range of ibis isolates collected in Western Australia was determined. The ibis isolates of Giardia were genetically relatively homogeneous, which is in contrast to the extensive genetic heterogeneity often displayed by mammalian Giardia isolates. Morphologically, Giardia from ibis were similar to Giardia ardeae although they differed genetically and by the fact that the ibis isolates could not be established in in vitro culture. Sequence data of the DNA coding for the SSU-rRNA found a 96% homology between the ibis isolates from Western Australia and G. ardeae, suggesting that they represent distinct strains of the same species. In contrast, the ibis isolates were genetically and morphologically very different than Giardia duodenalis and Giardia muris from mammals.
The restricted ability of most proteins and peptides to cross the blood-brain barrier and/or plasma membrane limits their use as therapeutics following cerebral ischaemia. However, the discovery of cell-penetrating peptides has provided a means by which such molecules can be transported across the blood-brain barrier and plasma membrane. Many proteins/peptides have already been shown to have neuroprotective properties, and, due to their ability to block protein-protein interactions, provide a potentially rich source of new therapeutic compounds to prevent cell death following cerebral ischaemia. In this review, we give an overview of cell-penetrating peptides and their use experimentally to deliver neuroprotectant proteins/peptides into the brain following cerebral ischaemia.
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.
There are virtually no clinically available neuroprotective drugs for the treatment of acute and chronic neurological disorders, hence there is an urgent need for the development of new neuroprotective molecules. Cationic arginine-rich peptides (CARPs) are an expanding and relatively novel class of compounds, which possess intrinsic neuroprotective properties. Intriguingly, CARPs possess a combination of biological properties unprecedented for a neuroprotective agent including the ability to traverse cell membranes and enter the CNS, antagonize calcium influx, target mitochondria, stabilize proteins, inhibit proteolytic enzymes, induce pro-survival signaling, scavenge toxic molecules, and reduce oxidative stress as well as, having a range of anti-inflammatory, analgesic, anti-microbial, and anti-cancer actions. CARPs have also been used as carrier molecules for the delivery of other putative neuroprotective agents across the blood-brain barrier and blood-spinal cord barrier. However, there is increasing evidence that the neuroprotective efficacy of many, if not all these other agents delivered using a cationic arginine-rich cell-penetrating peptide (CCPPs) carrier (e.g., TAT) may actually be mediated largely by the properties of the carrier molecule, with overall efficacy further enhanced according to the amino acid composition of the cargo peptide, in particular its arginine content. Therefore, in reviewing the neuroprotective mechanisms of action of CARPs we also consider studies using CCPPs fused to a putative neuroprotective peptide. We review the history of CARPs in neuroprotection and discuss in detail the intrinsic biological properties that may contribute to their cytoprotective effects and their usefulness as a broad-acting class of neuroprotective drugs.
Aim: R18D is a poly-arginine peptide that has demonstrated neuroprotection in preclinical models of excitotoxicity, stroke, hypoxic-ischemic encephalopathy and traumatic brain injury. Here, we examined the peptide's uptake in serum. Materials & methods: Healthy, male Sprague–Dawley rats were intravenously administered either 1000 nmol/kg R18D (D-enantiomer of R18) or approximately 2.5 nmol/kg (36 ± 9 MBq) [18F]R18D, for serum and organ tissue uptake, respectively. Serum samples underwent mass spectrometric analysis to detect unbound R18D peptide. Animals administered [18F]R18D were subjected to positron emission tomography imaging. Results & conclusion: Free R18D was detected at 5 min post-infusion in serum samples. [18F]R18D was rapidly distributed to the kidney (6–7%ID/g), and a small fraction localized to the brain (0.115–0.123%ID/g) over a 60-min acquisition period.
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