Hydrocephalus in the H-Tx rat: a monogenic disease?

The H-Tx rat is a genetic model of hydrocephalus for which thereis a poor understanding of the mode of inheritance. Previous studies suggested a polygenicmode of inheritance but the breeding data to supportthis hypothesis have not been reported. In an attempt to clarify the hereditary mode we have analyzed the data from eight generations of H-Tx rats and four generations of cross-matings between H-Tx rats and Sprague-Dawley (SD) rats. In the H-Tx rat colony 113 of 129 random brother-sister matings (87.60%) produced hydrocephalic offspring, with males and females being equally affected. The overall incidence varied greatly with an average of 30. 35%. In matings with more than three litters, all mating pairs yielded hydrocephalic pups. In cross-matings both hydrocephalic and normal H-Tx rats were mated with normal SD rats. No hydrocephalus was observed in the first generation of 124 pups (F1). Subsequent brother-sister matings of F1 animals generated hydrocephalic pups in the F2 generation with a lower incidence (4.67% in hydrocephalic HTx/SD matings and 5.11% in normal HTx/SD matings, respectively) than in the H-Tx rat colony (30.35%). Back-cross-matings between F2 rats and normal H-Tx rats yielded an incidence of hydrocephalus higher than that of the cross-matings but lower than that of the H-Tx colony. These data strongly suggest that the H-Tx rat is a homozygous carrier of an autosomal recessive hydrocephalus gene with incomplete penetrance. Furthermore, the data clearly rule out sex-linked and polygenic modes of inheritance and provide further insight with respect to genetic inheritance of hydrocephalus.

Evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the H-Tx rat model.

Oxidative stress can contribute to many neurological disease processes. Because many events known to involve oxidative stress (infection, hemorrhage, brain trauma) are accompanied by hydrocephalus, the present study sought to evaluate the relationship between oxidative stress and the progression of hydrocephalus. Assays for reactive oxygen species (ROS), using dichlorofluorescein (DCF) fluorescence, and lipid peroxidation, using malondialdehyde (MDA), were performed on brain tissue from the cerebral cortex, cerebellum, basal ganglia, and hippocampus of 4-, 10-, and 25-day-old normal and hydrocephalic H-Tx rats. These rats inherit hydrocephalus at a rate of 30-50% and represent a unique model for studying the progression of hydrocephalus. When hydrocephalic and normal H-Tx rats were compared, ROS levels were significantly higher in the cerebral cortex of 4-day-old and in the cerebellum and hippocampus of 4- and 10-day-old hydrocephalic rats. ROS levels also were significantly higher in the basal ganglia of 25-day-old hydrocephalic rats. MDA levels were significantly higher in the hippocampus and basal ganglia of 25-day-old hydrocephalic rats. There were no significant differences in MDA levels at younger ages. These results indicate that, in H-Tx rats, oxidative stress is associated with the progression and molecular pathophysiology of hydrocephalus. This association suggests that oxidative brain damage may represent an important factor resulting from or contributing to the pathogenesis of hydrocephalus.

Chronic nicotine treatment prevents neuronal loss in neocortex resulting from nucleus basalis lesions in young adult and aged rats.

In both young adult and aged rats, we tested the ability of chronically administered nicotine to rescue neocortical neurons from transneuronal degeneration resulting 5 mo after ibotenic acid (IBO) lesioning of the nucleus basalis magnocellularis (NBM). Young adult (2-3 mo-old) and aged (20-22-mo-old) rats were given unilateral infusions of IBO (5 mu g/1 mu L) at two sites within the NBM. Following surgery, animals began receiving either daily ip injections of nicotine (0.2 mg/kg) or saline vehicle. Treatment continued for 5 mo, at which time all animals were sacrificed and their brains processed histologically. For each brain, computer-assisted image analysis was then used to analyze the unlesioned (left) and lesioned (right) side of five non-consecutive brain sections from parietal cortex Layers II-IV and V. NBM lesioning in both young adult and aged vehicle-treated rats resulted in a significant 16-21% neuronal loss ipsilateral to NBM lesioning in neocortical Layers II-IV. Aged NBM-lesioned rats also exhibited a significant 12% neuronal loss in neocortical Layer V ipsilaterally. By contrast, those NBM-lesioned young adult and aged rats that received daily nicotine treatment postsurgery did not show any ipsilateral neuronal loss in the same parietal cortex areas, indicating that chronic nicotine treatment prevented the transneuronal degeneration of neocortical neurons resulting 5 mo afer NBM lesioning.

Antioxidant treatment with phenyl-alpha-tert-butyl nitrone (PBN) improves the cognitive performance and survival of aging rats.

Accumulating evidence has implicated free radical production and resultant oxidative damage as a major contributing factor in brain aging and cognitive decline. In the present study, aging 24-month-old rats were chronically treated with the synthetic spin-trapping antioxidant phenyl-alpha-tert-butyl nitrone (PBN) for up to 9.5 months. Chronic PBN treatment (1) improved the cognitive performance of aged rats in several tasks, (2) resulted in greater survival during the treatment period, and (3) decreased oxidative damage within brain areas important for cognitive function. These results not only provide a direct linkage between free radicals/oxidative damage and cognitive performance in old age, but also suggest that synthetic brain antioxidants could be developed to treat or prevent age-associated cognitive impairment and Alzheimer's disease.

Peptide T prevents NBM lesion-induced cortical atrophy in aged rats.

Because VIP is known to be neurotrophic in vitro, the present study tested whether peptide T (PT), an octapeptide with a pentapeptide sequence homologous to VIP, could prevent nucleus basalis (NBM)-induced degenerative changes in the parietal neocortex of aged rats. Aged (20-21 months old) Sprague-Dawley rats were given bilateral neurotoxic lesions of the NBM, and injected daily with PT (1 mg, IP) or vehicle solution for 5 months. Compared to unoperated controls, vehicle-treated NBM lesioned animals had: 1) a significant 17% decrease in overall cortical thickness, 2) significant decreases of 13-29% in the thickness of cortical layers II-IV, V, and VI, and 3) significant neuronal and glial cell loss in layer V. PT treatment prevented or attenuated these lesion-induced decreases in cortical thickness and attenuated the accompanying loss of large neurons in layer V. These results provide evidence that PT1 perhaps acting via VIP receptor stimulation, is neurotrophic and important for the integrity of brain tissue following denervation.

Chronic antioxidant treatment improves the cognitive performance of aged rats.

Free radicals and oxidative damage have been implicated in brain aging and several neurodegenerative diseases. The purpose of the present study was to determine whether antioxidants could alleviate age-associated cognitive and motor changes. Aged 24-month-old male Sprague-Dawley rats were treated for 4-5 months with daily i.p. injections of spin-trapping compound phenyl-alpha-tert-butylnitrone (PBN; 32 mg/kg) and alpha-tocopherol (200 mg/kg) or with vehicles. Antioxidant-treated animals also received ascorbate in their drinking water. In Morris water maze testing after two months, antioxidant-treated rats exhibited significantly greater memory retention than vehicle-treated rats in water maze testing. Subsequent tests for passive avoidance behavior and motor activity/skill revealed no effect of antioxidant treatment. In a separate group of aged 33-month-old rats that received the same combination of antioxidants for only 14 days, antioxidant treatment did not affect basal levels of brain lipid peroxidation (as indexed by TBAR formation) compared to controls. The results of this study provide initial evidence that chronic antioxidant treatment can improve cognitive function during aging, thus supporting the 'free radical hypothesis of aging' related to brain function.

Nicotine enhances Morris water maze performance of young and aged rats.

We have recently demonstrated that nicotine administration improves the acquisition and/or memory retention of aged rats in 17-arm radial maze, Lashley III maze, and one-way active avoidance testing. The present study extends our evaluation of nicotine's cognition-enhancing potential by determining the effect of nicotine on acquisition and retention of the Morris water maze in young adult (2 to 3 months old) and aged (25 to 26 months old) Sprague-Dawley rats. For 3 days prior to the onset of testing, and 15 min prior to daily testing, rats were treated IP with 0.2 mg/kg nicotine or saline vehicle. Compared to the performance of young adults, vehicle-treated aged rats were impaired in water maze acquisition. Nicotine substantially enhanced the acquisition of aged rats. Furthermore, nicotine significantly improved the memory retention of young adult rats. These cognitive improvements may involve a nicotine-receptor induced increase in generalized alertness and/or a facilitation of higher integrative function. The results suggest that nicotine and/or nicotinic agonists may be useful in treating age-associated memory impairment and/or Alzheimer's disease.