Proliferative and nonproliferative lesions of the rat and mouse male reproductive system.

The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the male reproductive system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the Internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the male reproductive system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.

Kainic acid-induced F-344 rat model of mesial temporal lobe epilepsy: gene expression and canonical pathways.

Mesial temporal lobe epilepsy (MTLE) is a severe neurological condition of unknown pathogenesis for which several animal models have been developed. To obtain a better understanding of the underlying molecular mechanisms and identify potential biomarkers of lesion progression, we used a rat kainic acid (KA) treatment model of MTLE coupled with global gene expression analysis to examine temporal (four hours, days 3, 14, or 28) gene regulation relative to hippocampal histopathological changes. The authors recommend reviewing the companion histopathology paper (Sharma et al. 2008) to get a better understanding of the work presented here. Analysis of filtered gene expression data using Ingenuity Pathways Analysis (Ingenuity Systems, http://www.ingenuity.com) revealed that a number of genes pertaining to neuronal plasticity (RhoA, Rac1, Cdc42, BDNF, and Trk), neurodegeneration (Caspase3, Calpain 1, Bax, a Cytochrome c, and Smac/Diablo), and inflammation/immune-response pathways (TNF-alpha, CCL2, Cox2) were modulated in a temporal fashion after KA treatment. Expression changes for selected genes known to have a role in neuronal plasticity were subsequently validated by quantitative polymerase chain reaction (qPCR). Notably, canonical pathway analysis revealed that a number of genes within the axon guidance signaling canonical pathway were up-regulated from Days 3 to 28, which correlated with aberrant mossy fiber (MF) sprouting observed histologically beginning at Day 6. Importantly, analysis of the gene expression data also identified potential biomarkers for monitoring neurodegeneration (Cox2) and neuronal/synaptic plasticity (Kalrn).

Temporal profile of clinical signs and histopathologic changes in an F-344 rat model of kainic acid-induced mesial temporal lobe epilepsy.

Since there is limited information in the literature, the purpose of this study was to investigate clinical signs, morphology, and temporal progression of lesions from Days 3 to 168 in a kainic acid (KA)-induced Fischer-344 (F-344) rat model of mesial temporal lobe epilepsy (MTLE). Following a single KA subcutaneous dose of 9 mg/kg to young adult male rats, 95% survived, 93% exhibited status epilepticus, and 80% eventually developed spontaneous motor seizures. Histopathology included hematoxylin and eosin (H&E), autofluorescence, Fluoro-Jade B, Timm's, ED-1/CD68, GFAP, doublecortin, and Ki-67. Neuronal degeneration occurred on Day 3 in the hippocampal CA1, CA3, and dentate hilar regions; amyg-daloid and thalamic nuclei; and frontoparietotemporal, entorhinal and piriform cortices. Degeneration severity peaked on Day 6 and decreased progressively until Day 168. Aberrant mossy fiber (MF) sprouting was present in the inner molecular layer of dentate gyrus on Days 6-168. Microliosis and astrogliosis peaked on Day 28 and generally colocalized with the distribution of neuronal degeneration. Important correlates to human MTLE included induction of spontaneous seizures, more severe neuronal damage of CA1 than CA3 (in contrast to other animal models but similar to humans), hilar neuronal loss, activated microgliosis and astrogliosis, aberrant MF sprouting, and dentate granule cell neurogenesis. Aberrant MF sprouting prior to spontaneous motor seizures and reduced seizure frequency with a decrease in aberrant MF sprouting support the hypothesis that MF sprouts are necessary for spontaneous seizure generation and maintenance.

Mesial temporal lobe epilepsy: pathogenesis, induced rodent models and lesions.

Mesial temporal lobe epilepsy (MTLE), the most common epilepsy in adults, is generally intractable and is suspected to be the result of recurrent excitation or inhibition circuitry. Recurrent excitation and the development of seizures have been associated with aberrant mossy fiber sprouting in the hippocampus. Of the animal models developed to investigate the pathogenesis of MTLE, post-status epilepticus models have received the greatest acceptance because they are characterized by a latency period, the development of spontaneous motor seizures, and a spectrum of lesions like those of MTLE. Among post-status epilepticus models, induction of systemic kainic acid or pilocarpine-induced epilepsy is less labor-intensive than electrical-stimulation models and these models mirror the clinicopathologic features of MTLE more closely than do kindling, tetanus toxin, hyperthermia, post-traumatic, and perinatal hypoxia/ischemia models. Unfortunately, spontaneous motor seizures do not develop in kindling or adult hyperthermia models and are not a consistent finding in tetanus toxin-induced or perinatal hypoxia/ischemia models. This review presents the mechanistic hypotheses for seizure induction, means of model induction, and associated pathology, especially as compared to MTLE patients. Animal models are valuable tools not only to study the pathogenesis of MTLE, but also to evaluate potential antiepileptogenic drugs.

A 6-month inhalation study to characterize the toxicity, pharmacokinetics, and pharmacodynamics of human insulin inhalation powder (HIIP) in beagle dogs.

The purpose of this study was to characterize the toxicity, pharmacokinetics, and pharmacodynamics of human insulin inhalation powder (HIIP) in beagle dogs when administered daily as an aerosolized dry powder formulation for 26 weeks via head-only inhalation. Conscious beagle dogs were exposed for 15 mins/day to an air control, placebo, maximal placebo (approximately three-fold the placebo dose), or one of three doses of HIIP (mean inhaled doses of 80, 240, or 701 microg/kg/day for the HIIP-low, HIIP-mid, and HIIP-high dose, respectively), The mass median aerodynamic diameters (MMAD) were between 2 and 3 microm and geometric standard deviation (GSD) values were approximately 2 across the groups, which is the ideal size range for favorable lung deposition. All groups were comprised of four dogs/sex, with the air control, HIIP-high, and maximal placebo groups having an additional two dogs/sex as recovery subgroups. Concentrations of serum insulin and glucose were determined from blood samples obtained following the first and last exposure for evaluation of the pharmacokinetics and pharmacodynamics of HIIP. Dose-related exposure (C(max), AUC) to inhaled insulin was observed with rapid absorption and no apparent gender differences or accumulation after repeated inhalation exposures for 26 weeks. The expected pharmacological effect of insulin was observed with dose-related decreases in serum glucose levels following HIIP administration. There were no toxic effects observed including no HIIP or placebo treatment-related effects on mean body weights, absolute body weight changes, clinical observations, food consumption, respiratory function parameters, ophthalmic examinations, electrocardiograms, heart rates, clinical pathology, or urinalysis. Similarly, there were no HIIP or placebo treatment-related effects on pulmonary assessments that included respiratory function parameters, bronchial alveolar lavage assessments, organ weights, or macroscopic and microscopic evaluations, including lung cell proliferation indices. HIIP was considered to have either low or no immunogenic potential in dogs. The no-observed-adverse-effect level (NOAEL) and maximum tolerated dose were the average inhaled dose of 701 microg insulin/kg/day.

Development of a percutaneous cerebrospinal fluid collection technique in F-344 rats and evaluation of cell counts and total protein concentrations.

A simple technique for cerebrospinal fluid (CSF) collection was developed in F-344 rats. Cell counts and total protein concentrations were evaluated to assess sample quality. While the 50 to 70 mu L samples of CSF collected on three different days showed a progressive decrease in the total erythrocyte and nucleated cell counts, no significant changes were observed in the total protein concentrations. Progressive decreases in the total erythrocyte count correlated positively with the decreases in volume of CSF collected. Our data suggest that collection of less than 50 mu L of CSF will give a better quality of CSF in F-344 rats. This is the first report of cellular and protein parameters in the CSF of F-344 rats.