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D F Emerich

Publications and source records attributed to D F Emerich.

94 records · Page 6Linked to original sources
PubMedDate not supplied

Cellular delivery of CNTF but not NT-4/5 prevents degeneration of striatal neurons in a rodent model of Huntington's disease.

The delivery of neurotrophic factors to the central nervous system (CNS) has gained considerable attention as a potential treatment strategy for neurodegenerative disorders such as Huntington's disease (HD). In the present study, we directly compared the ability of two neurotrophic factors, ciliary neurotrophic factor (CNTF), and neurotrophin-4/5 (NT-4/5), to prevent the degeneration of striatal neurons following intrastriatal injections of quinolinic acid (QA). Expression vectors containing either the human CNTF or NT-4/5 gene were transfected into a baby hamster kidney fibroblast cell line (BHK). Using a polymeric device, encapsulated BHK-control cells and those secreting either CNTF (BHK-CNTF) or NT-4/5 (BHK-NT-4/5) were transplanted unilaterally into the rat lateral ventricle. Seven days later, the same animals received unilateral injections of QA (225 nmol) into the ipsilateral striatum. Nissl-stained sections demonstrated that the BHK-CNTF cells significantly reduced the volume of striatal damage produced by QA. Quantitative analysis of striatal neurons further demonstrated that both choline acetyltransferase (ChAT)- and glutamic acid decarboxylase (GAD)-immunoreactive neurons were protected by CNTF implants. In contrast, the volume of striatal damage and loss of striatal ChAT and GAD-positive neurons in animals receiving BHK-NT-4/5 implants did not differ from control-implanted animals. These results help better define the scope of neuronal protection that can be afforded following cellular delivery of various neurotrophic factors. Moreover, these data further support the concept that implants of polymer-encapsulated CNTF-releasing cells can be used to protect striatal neurons from excitotoxic damage, and that this strategy may ultimately prove relevant for the treatment of HD.

Animals↗
PubMedDate not supplied

Biocompatibility of poly (DL-lactide-co-glycolide) microspheres implanted into the brain.

The delivery of therapeutic molecules to the brain has been limited in part due to the presence of the blood-brain barrier. One potential solution is the implantation of biodegradable polymers with sustained release of drugs. Poly (DL-lactide-co-glycolide) (PLG) is a bioerodible polymer with a long and successful history of use as a suture material. More recently, PLG has been investigated for localized and sustained delivery of molecules into both peripheral sites and the brain. Despite its well-defined safety profile for parenteral applications, little information exists concerning the safety of PLG when implanted into the brain. To further characterize the biocompatibility of PLG in the brain, we examined the gliotic response following implants of PLG into the brains of rats. As a control, each animal received an injection of the suspension medium into the contralateral hemisphere. Following implantation, PLG was well tolerated. GFAP-positive astrocytes were observed throughout the cerebral cortex and striatum on both the implanted and control sides, with the reaction being greatest within the heavily myelinated fiber tracts of the corpus callosum. Quantitative analyses revealed that this reaction occurred within 1 h postsurgery, reached its peak at 1 week following surgery, and then decreased markedly by 1 month postsurgery. A minimal gliotic reaction was still present 1 year postsurgery but was localized to the needle tract. No differences in GFAP reactivity were seen between the polymer-implanted and control sides at any time point. Histological analysis determined that the majority of the PLG disappeared between 1 and 4 weeks. A set of parallel studies in which PLG samples were retrieved from the brain at various time points corroborated these findings and determined that the majority of PLG degraded within 2 weeks following implantation. Together, these results demonstrate that PLG is well tolerated following implantation into the CNS and that the astrocytic response to PLG is largely a consequence of the mechanical trauma that occurs during surgery. The biocompatibility of PLG implanted into the CNS provides further support for its use in a wide range of new therapeutic applications for sustained and localized drug delivery to the brain.

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PubMedDate not supplied

Update on immunoisolation cell therapy for CNS diseases.

Delivery of potentially therapeutic drugs to the brain is hindered by the blood-brain barrier (BBB), which restricts the diffusion of drugs from the vasculature to the brain parenchyma. One means of overcoming the BBB is with cellular implants that produce and deliver therapeutic molecules. Polymer encapsulation, or immunoisolation, provides a means of overcoming the BBB to deliver therapeutic molecules directly into the CNS region of interest. Immunoisolation is based on the observation that xenogeneic cells can be protected from host rejection by encapsulating, or surrounding, them within an immunoisolatory, semipermeable membrane. Cells can be enclosed within a selective, semipermeable membrane barrier that admits oxygen and required nutrients and releases bioactive cell secretions, but restricts passage of larger cytotoxic agents from the host immune defense system. The selective membrane eliminates the need for chronic immunosuppression of the host and allows the implanted cells to be obtained from nonhuman sources. In this review, cell immunoisolation for treating CNS diseases is updated from considerations of device configurations, membrane manufacturing and characterization in preclinical models of Alzheimer's and Huntington's disease.

Alzheimer Disease↗