Neuroprotective Potential of Biphalin, Multireceptor Opioid Peptide, Against Excitotoxic Injury in Hippocampal Organotypic Culture

Biphalin is a dimeric opioid peptide that exhibits affinity for three types of opioid receptors (MOP, DOP and KOP). Biphalin is undergoing intensive preclinical study. It was recognized that activation of δ-opioid receptor elicits neuroprotection against brain hypoxia and ischemia. We compare the effect of biphalin and morphine and the inhibition of opioid receptors by naltrexone on survival of neurons in rat organotypic hippocampal cultures challenged with NMDA. Findings: (1) 0.025–0.1 μM biphalin reduces NMDA-induced neuronal damage; (2) biphalin neuroprotection is abolished by naltrexone; (3) reduced number of dead cells is shown even if biphalin is applied with delay after NMDA challenge

Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches

International audienceFor several decades, the treatment of central nervous system (CNS) disorders such as, for instance, Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) represented an important challenge due to the difficulty in delivering drug molecules and imaging agents to the brain. Two strategies have been developed aimed at achieving the efficient delivery of drugs to the brain: invasive (e.g., temporary osmotic Blood Brain Barrier (BBB) opening, direct local delivery of nanoparticles with encapsulated CNS drugs etc.) and noninvasive approaches. As a part of the noninvasive approach among systemic delivery of drug molecules across BBB using nanocarriers, dendrimers represent promising therapeutics agents per se or nanocarriers of CNS drugs and for gene therapies. This original review emphasizes and analyzes the use of dendrimers as promising systems in the treatment of AD and PD, ischemia/reperfusion injury, neuroinflammation including cerebral palsy, neurological injury after cardiac surgery and particularly after hypothermic circulatory arrest, and for retinal degeneration purposes

A strong neuroprotective effect of the autonomous Cterminal peptide of IGF-1 Ec (MGF) in brain ischemia

Published online September 6, 2005 ©2005 FASEBThe ischemic stroke is the third leading cause of death in developed countries. The C-terminal peptide of mechano-growth factor (MGF), an alternatively spliced variant of insulin-like growth factor 1 (IGF-1), was found to function independently from the rest of the molecule and showed a neuroprotective effect in vivo and in vitro. In vivo, in a gerbil model of transient brain ischemia, treatment with the synthetic MGF C-terminal peptide provided very significant protection to the vulnerable neurons. In the same model, ischemia evoked increased expression of endogenous MGF in the ischemia-resistant hippocampal neurons, suggesting that the endogenous MGF might have an important neuroprotective function. In an in vitro organotypic hippocampal culture model of neurodegeneration, the synthetic peptide was as potent as the full-length IGF-1 while its effect lasted significantly longer than that of recombinant IGF-1. While two peptides showed an additive effect, the neuroprotective action of the C-terminal MGF was independent from the IGF-1 receptor, indicating a new mode of action for this molecule. Although MGF is known for its regenerative capability in skeletal muscle, our findings demonstrate for the first time a neuroprotective role against ischemia for this specific IGF-1 isoform. Therefore, the C-terminal MGF peptide has a potential to be developed into a therapeutic modality for the prevention of neuronal damage.Joanna Dluzniewska, Anna Sarnowska, Malgorzata Beresewicz, Ian Johnson, Surjit K. S. Srai, Bala Ramesh, Geoffrey Goldspink, Dariusz C. Górecki, and Barbara Zablock

RPGRIP1L mutations are mainly associated with the cerebello-renal phenotype of Joubert syndrome-related disorders

Joubert syndrome-related disorders (JSRDs) are autosomal recessive pleiotropic conditions sharing a peculiar cerebellar and brainstem malformation known as the 'molar tooth sign' (MTS). Recently, mutations in a novel ciliary gene, RPGRIP1L, have been shown to cause both JSRDs and Meckel-Gruber syndrome. We searched for RPGRIP1L mutations in 120 patients with proven MTS and phenotypes representative of all JSRD clinical subgroups. Two homozygous mutations, the previously reported p.T615P in exon 15 and the novel c.2268_2269delA in exon 16, were detected in 2 of 16 families with cerebello-renal presentation (similar to 12%). Conversely, no pathogenic changes were found in patients with other JSRD phenotypes, suggesting that RPGRIP1L mutations are largely confined to the cerebello-renal subgroup, while they overall represent a rare cause of JSRD (< 2%)