Transmitter-loaded polymeric microspheres induce regrowth of dopaminergic nerve terminals in striata of rats with 6-OH-DA induced parkinsonism.
Biodegradable controlled-release microspheres made with the biocompatible biodegradable polyester excipient poly (DL-lactide-co-glycolide) represent a new technology for drug delivery to the central nervous system (CNS). A suspension of 3 microliters of dopamine (DA) or NE containing microspheres, or empty microspheres, was implanted in 2 sites of the DA denervated striatum of rats previously unilaterally lesioned with 6-OH-DA. Contralateral rotational behavior induced by apomorphine was used as an index of lesion success. Following implantation of the microspheres, rotational behavior was also used as an index of functional recovery. Both DA and NE microsphere implanted rats displayed a 30-50% reduction in the number of apomorphine induced rotations up to 12 weeks post implantation. Empty microspheres caused no changes in rotational behavior. Implantation of a mixture of DA/NE microspheres resulted in an 80% decrease in the number of apomorphine induced rotations, registered up to 4 weeks. Immunocytochemical examination revealed growth of DA and tyrosine hydroxylase immunoreactive fibers in the striatum of DA and NE microsphere implanted rats. Interestingly, functional behavior correlated with the degree of fiber ingrowth. This method to deliver substances to the CNS will be tested for therapeutic usefulness in patients with Parkinson's disease, in a recently approved clinical trial in Göteborg.
McRae
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Department of Anatomy and Cell Biology (Neurobiology), NRCG, University of Göteborg, Sweden.
Dahlström
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D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002214:Capsules; D004298:Dopamine / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D007150:Immunohistochemistry; D019344:Lactic Acid; D008297:Male; D008863:Microspheres; D017072:Neostriatum / Q000166:cytology / Q000254:growth & development / Q000473:pathology*; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology*; D009412:Nerve Fibers / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology* / Q000523:psychology; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects
D002214:Capsules; D018377:Neurotransmitter Agents; D011108:Polymers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D016627:Oxidopamine; D001058:Apomorphine; D004298:Dopamine; D009638:Norepinephrine