Effects of frontal cortical lesions on mouse striatum: reorganization of cell recognition molecule, glial fiber, and synaptic protein expression in the dorsomedial striatum

Brain injury induces trophic effects within adjacent tissue through an unknown molecular mechanism. One model of this lesion effect involves the enhanced outgrowth of neuronal processes from transplanted substantia nigra in animals with cerebral cortex lesions. Since cell recognition molecules are involved in the molecular mechanisms of contact between cells and surrounding extracellular matrix components, and are important in plasticity of the nervous system, we investigated changes in L1, N-CAM, and tenascin, as well as synapse-associated proteins and gliosis, in the striatum of mice with cortical lesions. The removal of somato-sensory and motor cortex would be expected to produce changes predominantly in the dorsal striatum. Lesioned mice, however, showed a significant enhancement of both L1 and N-CAM immunostaining intensity only within the most medial-periventricular and dorsomedial parts of the striatum, as compared to the nonlesioned side. Tenascin expression was significantly decreased, but only in the most medial part of the striatum. The changes in intensity of immunostaining with L1, N-CAM, and tenascin did not diminish with time after lesioning. These changes in cell recognition molecule expression indicate a possible molecular basis of lesion-induced plasticity in neuronal circuits within the dorsomedial striatum. These changes were accompanied by decreased synapsin and synaptophysin expression, but without any significant change in neurofilament expression. In contrast, glial fibrillary acidic protein and vimentin immunoreactivities were increased in almost the entire striatum on the lesioned side. Therefore, the areas of changes in cell recognition molecule expression did not simply correlate to the increased astrogliosis or neuronal fiber damage. We postulate that the periventricular dorsomedial striatum is relatively sensitive to disturbances of corticostriatonigral circuits and, simultaneously, this striatal area has a unique ability to support and promote neurite growth

Superior cervical ganglion regenerating axons through peripheral nerve grafts and reversal of behavioral deficits in hemiparkinsonian rats

The superior cervical ganglion (SCG) has been grafted to the brain of adult rats in an attempt to reverse the parkinsonian syndrome that follows destruction of central dopamine systems. However, the main limitation to this approach is the massive cell death that occurs in the grafted SCG after direct transplantation into the brain. In adult rats, 6-hydroxydopamine (6-OHDA) was stereotactically injected into the right substantia nigra (SN). One month later, dopamine denervation was assessed using the apomorphine-induced rotational test. In rats with a positive test, an autologous peripheral nerve (PN) graft was tunneled from the right cervical region to the ipsilateral parietal cortex. One end of PN graft was sutured to the transected postganglionic branch of the SCG and the other end was inserted into a surgically created cortical cavity. The apomorphine test was repeated at 3 days and again at 1, 3, and 5 months after surgery. The brain, SCG, and PN graft were studied under light and electron microscopy and with the tyrosine hydroxylase immunohistochemical and horseradish peroxidase tracing methods. Three days after grafting, there were no significant differences on the apomorphine test as compared to the preoperative test. Conversely, 1,3, and 5 months after grafting, the number of rotations was reduced by 69% (+/-20.2), 66.6% (+/-17.1), and 72.5% (+/-11.3), respectively. Control rats that received a free PN graft to the brain and underwent section of the postganglionic branch of the SCG did not show significant changes on the apomorphine test after surgery. Histological examination revealed that the PN graft was mostly reinnervated by amyelinic axons of small caliber. Approximately 40% of the SCG neuronal population that normally projects to the postganglionic branch survived axotomy and regenerated the transected axons into the PN graft. Axons arising from the SCG elongated the whole length of the graft, crossed the graft-brain interface and extended into brain regions adjacent to the denervated striatum up to 2037 micrometer from the graft insertion site. This work shows that the ingrowth of catecholamine-regenerating axons from the SCG to dopamine-depleted brain parenchyma significantly reduces behavioral abnormalities in hemiparkinsonian rats. This effect cannot be ascribed either to the brain cavitation or to the PN tissue placement in the brain

Drug Metabolism

Absorption, Distribution, Metabolism and Excretion (ADME) processes and their relationship with the design of dosage forms and the success of pharmacotherapy form the basis of this upper level undergraduate/graduate textbook. As an introduction oriented to pharmacy students, it is also written for scientist from different fields outside of pharmaceutics. (e.g. material scientist, material engineers, medicinal chemists) who might be working in a positions in pharmaceutical companies or whose work might benefit from basic training in the ADME concepts and some biological background. Pedagogical features such as objectives, keywords, discussion questions, summaries and case studies add valuable teaching tools. This book will provide not only general knowledge on ADME processes but also an updated insight on some hot topics such as drug transporters, multi-drug resistance related to pharmacokinetic phenomena, last generation pharmaceutical carriers (nanopharmaceuticals), in vitro and in vivo bioequivalence studies, biopharmaceuticals, pharmacogenomics, drug-drug and food-drug interactions, and in silico and in vitro prediction of ADME properties. In comparison with other similar textbooks, around half of the volume would be focused on the relationship between expanding scientific fields and ADME processes. Each of these burgeoning fields has a separate chapter in the second part of the volume, and was written with leading experts on the correspondent topic, including scientists and academics from USA and UK (Duquesne University School of Pharmacy, Indiana University School of Medicine, University of Utah College of Pharmacy, University of Maryland, University of Bath).Additionally, each of the initial chapters dealing with the generalities of drug absorption, distribution, metabolism and excretion would include relevant, classic examples related to each topic with appropriate illustrations (e.g. importance of active absorption of levodopa, implications in levodopa administration, drug drug interactions and food drug interactions emerging from the active uptake; intoxication with paracetamol as a result of glutathione depletion, CYP induction and its relationship with acute liver failure caused by paracetamol, etc).ADME Processes and Pharmaceutical Sciences is written as a core textbook for ADME processes, pharmacy, pharmacokinetics, drug delivery, biopharmaceutics, drug disposition, drug design and medicinal chemistry courses.Fil: Talevi, Alan. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Bellera, Carolina Leticia. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin