Use of Anisotropy, 3D Segmented Atlas, and Computational Analysis to Identify Gray Matter Subcortical Lesions Common to Concussive Injury from Different Sites on the Cortex.

Traumatic brain injury (TBI) can occur anywhere along the cortical mantel. While the cortical contusions may be random and disparate in their locations, the clinical outcomes are often similar and difficult to explain. Thus a question that arises is, do concussions at different sites on the cortex affect similar subcortical brain regions? To address this question we used a fluid percussion model to concuss the right caudal or rostral cortices in rats. Five days later, diffusion tensor MRI data were acquired for indices of anisotropy (IA) for use in a novel method of analysis to detect changes in gray matter microarchitecture. IA values from over 20,000 voxels were registered into a 3D segmented, annotated rat atlas covering 150 brain areas. Comparisons between left and right hemispheres revealed a small population of subcortical sites with altered IA values. Rostral and caudal concussions were of striking similarity in the impacted subcortical locations, particularly the central nucleus of the amygdala, laterodorsal thalamus, and hippocampal complex. Subsequent immunohistochemical analysis of these sites showed significant neuroinflammation. This study presents three significant findings that advance our understanding and evaluation of TBI: 1) the introduction of a new method to identify highly localized disturbances in discrete gray matter, subcortical brain nuclei without postmortem histology, 2) the use of this method to demonstrate that separate injuries to the rostral and caudal cortex produce the same subcortical, disturbances, and 3) the central nucleus of the amygdala, critical in the regulation of emotion, is vulnerable to concussion.

A phenotypic model recapitulating the neuropathology of Parkinson's disease.

This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8-9 month old, ovariectomized Long-Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11-12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5-6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2'-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the identification of biomarkers to identify patients in early stage, PD.

Quantitative structure­property relationships of camptothecins in humans.

PURPOSE: To develop quantitative structure property relationships (QSPR) for the pharmacokinetics and the susceptibility to BCRP-mediated efflux of ten drugs in the camptothecin family of topoisomerase I inhibitors. METHODS: Pharmacokinetic parameters (total and lactone clearance, total steady-state volume of distribution, and lactone:total area under the curve ratio) and IC(50) values of cytotoxicity in both BCRP over-expressing and sensitive cell lines were extracted from the literature. Molecular descriptors were generated for both the lactone and carboxylic acid forms of the drugs using SYBYL and ACD/Labs software. A partial least squares algorithm in SAS was used to construct QSPR models for each of the properties of interest, and final models were validated using leave-one-out cross-validation. RESULTS: The molecular descriptors calculated for the lactone forms were better correlated with the selected properties than that of the carboxylate forms. Reasonable correlations (R(2) range 0.63-0.99) and good predictive performances (Q(2) range 0.45-0.88) were obtained for all seven QSPR models. Molecular descriptors that contribute to each pharmacokinetic property and susceptibility to BCRP mediated efflux were identified. CONCLUSIONS: QSPR models were successfully constructed for the pharmacokinetics and the susceptibility to BCRP mediated efflux of the camptothecin analogs. The identified molecular parameters may help guide the synthesis of new camptothecin analogs with improved pharmacokinetic properties and reduced potential for clinical resistance.

Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases.

With an increase in lifespan and changing population demographics, the incidence of central nervous system (CNS) diseases is expected to increase significantly in the 21st century. The most challenging of the CNS diseases are neurodegenerative diseases, characterized by age-related gradual decline in neurological function, often accompanied by neuronal death. Alzheimer's disease, Parkinson's disease and Huntington's disease are some examples of neurodegenerative diseases and have been well described in terms of disease mechanisms and pathology. However, successful treatment strategies for neurodegenerative diseases have so far been limited. Delivery of drugs into the CNS is one of the most challenging problems faced in the treatment of neurodegeneration. In this review, we describe the difficulties with CNS therapy, especially with the use of biological macromolecules, such as proteins and nucleic acid constructs. CNS therapeutics also represents a huge opportunity and examples of strategies that can enhance therapeutic delivery for the treatment of neurodegenerative diseases are emphasized. It is anticipated that with an increase in biological understanding of neurodegenerative diseases, there will be even more therapeutic opportunities. As such, these delivery strategies have a very important role to play in the future in the translation of CNS therapeutics from bench to bedside.