Macrophage-mediated GDNF Delivery Protects Against Dopaminergic Neurodegeneration: A Therapeutic Strategy for Parkinson's Disease

Glial cell line–derived neurotrophic factor (GDNF) has emerged as the most potent neuroprotective agent tested in experimental models for the treatment of Parkinson''s disease (PD). However, its use is hindered by difficulties in delivery to the brain due to the presence of the blood–brain barrier (BBB). In order to circumvent this problem, we took advantage of the fact that bone marrow stem cell–derived macrophages are able to pass the BBB and home to sites of neuronal degeneration. Here, we report the development of a method for brain delivery of GDNF by genetically modified macrophages. Bone marrow stem cells were transduced ex vivo with lentivirus expressing a GDNF gene driven by a synthetic macrophage-specific promoter and then transplanted into recipient mice. Eight weeks after transplantation, the mice were injected with the neurotoxin, MPTP, for 7 days to induce dopaminergic neurodegeneration. Macrophage-mediated GDNF treatment dramatically ameliorated MPTP-induced degeneration of tyrosine hydroxylase (TH)-positive neurons of the substantia nigra and TH⁺ terminals in the striatum, stimulated axon regeneration, and reversed hypoactivity in the open field test. These results indicate that macrophage-mediated GDNF delivery is a promising strategy for developing a neuroprotective therapy for PD.     

Pluronic L-81 ameliorates diabetic symptoms in db/db mice through transcriptional regulation of microsomal triglyceride transfer protein

AIM： To test whether oral L-81 treatment could improve the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein （MTP） activity in the liver.
METHODS： Genetically diabetic （db/db） mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mechanism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B （apoB） secretion and mRNA level of the MTP gene were assessed.
RESULTS： Treatment of db/db mice with L-81 significantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also significantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter.
CONCLUSION： L-81 represents a promising candidate in the development of a selective insulin-mimetic molecule and an anti-diabetic agent.     

Induction of plasmacytomas secreting antigen-specific monoclonal antibodies with a retrovirus expressing v-abl and c-myc.

ABL-MYC, a recombinant murine retrovirus that expresses v-abl and c-myc, rapidly induces transplantable mono- or oligoclonal plasmacytomas in BALB/c mice. To determine if the targets for transformation of this retrovirus are antigen-committed B lymphocytes and to explore this system as an alternative technique for producing antigen-specific monoclonal antibodies, plasmacytomas were induced in mice that had been immunized with two different types of immunogens, hen egg white lysozyme and sheep red blood cells. The majority of these plasmacytomas secreted immunogen-specific antibodies. Plasmacytomas induced in unimmunized mice did not react with hen egg white lysozyme or sheep red blood cells. The specific antibodies were comparable in concentration, specificity, and affinity to monoclonal antibodies obtained with conventional hybridoma technology, but, in addition to IgGs and IgMs, they included specific IgA antibodies, which are rare among splenic-derived hybridomas. Our results demonstrate that a principal target for ABL-MYC is an antigen-committed B lymphocyte. In addition this procedure provides an alternative method for the production of monoclonal antibodies, without a requirement for hetero-caryon formation by cell fusion techniques.