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Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research.

Calorie restriction (CR) is a reliable anti-aging intervention that attenuates the onset of a number of age-related diseases, reduces oxidative damage, and maintains function during aging. In the current study, we assessed the effects of CR and other feeding regimens on wound healing in 7-month-old Fischer-344 rats from a larger cohort of rats that had been fed either ad libitum (AL) or 40% calorie restricted based on AL consumption. Rats were assigned to one of three diet groups that received three skin punch wounds along the dorsal interscapular region (12-mm diameter near the front limbs) of the back as follows: (1) CR (n = 8) were wounded and maintained on CR until they healed, (2) AL (n = 5) were wounded and maintained on AL until wound closure was completed, and (3) CR rats were refed (RF, n = 9) AL for 48 h prior to wounding and maintained on AL until they healed. We observed that young rats on CR healed more slowly while CR rats refed for 48 h prior to wounding healed as fast as AL fed rats, similar to a study reported in aged CR and RF mice (Reed et al. 1996). Our data suggest that CR subjects, regardless of age, fail to heal well and that provision of increased nutrition to CR subjects prior to wounding enhances the healing process.

Caloric restriction (CR) mitigates neurological damage arising from aging and a variety of other sources, including neuropathology in young adult mice that express single and double transgenic (tg) mutations associated with Alzheimer disease (AD). To evaluate the potential of CR to protect against relatively heavy AD-type pathology, middle-aged (13-14-month-old) mice that co-express two mutations related to familial AD, amyloid precursor protein (APP) and presenilin 1 (PS1), were fed balanced diets with 40% fewer calories than ad libitum-fed controls. Following 18 weeks of treatment, mice were killed and brains were processed for quantification of total volume of amyloid-beta (Abeta) in the hippocampal formation and the overlying neocortex. Computerized stereology confirmed that CR reduced the total Abeta volume by about one-third compared to that in age-matched controls. Thus, CR appears to attenuate the accumulation of AD-type neuropathology in two cortical brain regions of middle-aged dtg APP/PS1 mice. These findings support the view that CR could be a potentially effective, non-pharmacology strategy for reducing relatively heavy Abeta deposition in older adult dtg APP/PS1 mice, and possibly afford similar protection against the onset and progression of AD in older adult humans.

Progress in gerontological research has been promoted through the use of numerous animal models, which have helped identify possible mechanisms of aging and age-related chronic diseases and evaluate possible interventions with potential relevance to human aging and disease. Further development of nonhuman primate models, particularly rhesus monkeys, could accelerate this progress, because their closer genetic relationship to humans produces a highly similar aging phenotype. Because the relatively long lives of primates increase the administrative and economic demands on research involving them, new emphasis has emerged on increasing the efficient use of these valuable resources through cooperative, interdisciplinary research.

Aims/hypothesis: This study was designed to determine whether inhibition of formation of AGE and advanced lipoxidation end-products (ALE) is a mechanism of action common to a diverse group of therapeutic agents that limit the progress of diabetic nephropathy. We compared the effects of the ACE inhibitor enalapril, the antioxidant vitamin E, the thiol compound lipoic acid, and the AGE/ALE inhibitor pyridoxamine on the formation of AGE/ALE and protection against nephropathy in streptozotocin diabetic rats., Methods: Renal function and AGE/ALE formation were evaluated in rats treated with the agents listed above. Plasma was monitored monthly for triglycerides, cholesterol, creatinine and TNF-alpha, and 24-h urine samples were collected for measurement of albumin and total protein excretion. After 29 weeks, renal expression of mRNA for extracellular matrix proteins was measured, and AGE/ALE were quantified in skin and glomerular and tubular collagen., Results: Diabetic animals were both hyperglycaemic and dyslipidaemic, and showed evidence of early nephropathy (albuminuria, creatinaemia). All interventions limited the progression of nephropathy, without affecting glycaemia. The order of efficacy was: pyridoxamine (650 mg.kg(-1).day(-1)) > vitamin E (200 mg.kg(-1).day(-1)) > lipoic acid (93 mg.kg(-1).day(-1)) approximately enalapril (35 mg.kg(-1).day(-1)). Pyridoxamine also significantly inhibited AGE/ALE accumulation in tissues; effects of other agents were mixed, but the degree of renoprotection was consistent with their effects on AGE/ALE formation., Conclusions/interpretation: All interventions inhibited the progression of nephropathy at the doses studied, but the maximal benefit was achieved with pyridoxamine, which also limited dyslipidaemia and AGE/ALE formation. These experiments indicate that the more effective the renoprotection, the greater the inhibition of AGE/ALE formation. For optimal protection of renal function, it would be beneficial to select drugs whose mechanism of action includes inhibition of AGE/ALE formation.

The role of the claustrum in Pavlovian heart rate (HR) conditioning was studied in the rabbit (Oryctolagus cuniculus) by (a) mapping claustral projections to the prefrontal cortex (PFC), (b) recording claustral single-unit discharge to sensory stimulation and conditioning stimuli during HR conditioning, and (c) assessing the effects of claustral damage on HR conditioning. Contralateral and ipsilateral claustral projections to the PFC were found. Claustral cells responded to nonsignal stimulation with increased discharge and also showed conditioned stimulus-evoked increases in discharge during Pavlovian HR conditioning. Moreover, claustral lesions diminished the magnitude of the HR-conditioned response without affecting the cardiac-orienting response to the conditioned stimulus or the cardiac-unconditioning response to the unconditioned stimulus, suggesting a role for the claustrum in associative learning., (((c) 2004 APA, all rights reserved))

Maillard or browning reactions between reducing sugars and protein lead to formation of advanced glycation end products (AGEs) and are thought to contribute to the pathogenesis of diabetic complications. AGE inhibitors such as aminoguanidine and pyridoxamine (PM) inhibit both the formation of AGEs and development of complications in animal models of diabetes. PM also inhibits the chemical modification of protein by advanced lipoxidation end products (ALEs) during lipid peroxidation reactions in vitro. We show here that several PM adducts, formed in incubations of PM with linoleate and arachidonate in vitro, are also excreted in the urine of PM-treated animals. The PM adducts N-nonanedioyl-PM (derived from linoleate), N-pentanedioyl-PM, N-pyrrolo-PM, and N-(2-formyl)-pyrrolo-PM (derived from arachidonate), and N-formyl-PM and N-hexanoyl-PM (derived from both fatty acids) were quantified by liquid chromatography-mass spectrometry analysis of rat urine. Levels of these adducts were increased 5-10-fold in the urine of PM-treated diabetic and hyperlipidemic rats, compared with control animals. We conclude that the PM functions, at least in part, by trapping intermediates in AGE/ALE formation and propose a mechanism for PM inhibition of AGE/ALE formation involving cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions. We also conclude that ALEs derived from polyunsaturated fatty acids are increased in diabetes and hyperlipidemia and may contribute to development of long term renal and vascular pathology in these diseases.

Background: In previous studies, pyridoxamine (PM) limited the formation of advanced glycation end products (AGEs) and development of nephropathy in streptozotocin-diabetic rats without affecting glycemic control. However, the lipid-lowering effects of PM and the correlation of plasma cholesterol and triglycerides with AGEs in skin collagen suggested that lipids might be an important source of AGEs in the diabetic rat. This study addresses the effects of hyperlipidemia on formation of advanced glycation and lipoxidation end products (AGE/ALEs) and the effects of PM on hyperlipidemia, hypertension, AGE/ALE formation, and development of nephropathy in the nondiabetic, Zucker obese rat., Methods: Three groups of Zucker rats were studied: lean (Fa/fa), untreated fatty (fa/fa), and fa/fa treated with PM (2 g/L drinking water). Blood pressure, plasma lipids and creatinine, and urinary albumin were measured monthly. AGE/ALEs were measured in skin collagen by high-performance liquid chromatography (HPLC) and gas chromatography/mass spectrometry (GC/MS). Changes in wall thickness of the aorta and renal arterioles were evaluated by light microscopy., Results: AGE/ALEs formation was increased two- to threefold in skin collagen of obese versus lean rats. PM inhibited the increases in AGE/ALEs in collagen, and significantly decreased the rise in plasma triglycerides, cholesterol, and creatinine, corrected hypertension and thickening of the vascular wall, and nearly normalized urinary protein and albumin excretion in Zucker fa/fa rats., Conclusion: Lipids are an important source of chemical modification of tissue proteins, even in the absence of hyperglycemia. PM inhibited AGE/ALE formation and hyperlipidemia and protected against renal and vascular pathology in a nondiabetic model.

Drugs such as PCP and MK-801 can cause psychotic reactions in humans by antagonizing NMDA receptors. This action is ultimately toxic to certain cortical neurons and may be one mechanism underlying neurodegenerative diseases, including schizophrenia. It has been reported that hallucinogens such as LSD, DOM, and DOI can block the neurotoxic effects of NMDA antagonists, possibly by activating inhibitory 5-HT2A receptors on GABAergic interneurons that normally inhibit glutamatergic projections to the retrosplenial and cingulate cortexes. The purpose of this experiment was to determine the extent to which similar drugs might also alter the behavioral effects of one NMDA antagonist, PCP. Rats were trained to discriminate this compound (2.5 mg/kg) from saline and were then given a series of antagonist tests. It was found that LSD (0.32 mg/kg) and DOM (4.0 mg/kg) blocked the PCP cue completely; DMT (8.0 mg/kg) and a structural congener of LSD, lisuride (LHM; 0.4 mg/kg), blocked the effects of PCP partially. The 5-HT/DA antagonists spiperone and ritanserin had no effect on the PCP cue. These data suggest that LSD, DOM, and, less effectively, DMT and LHM can block the behavioral as well as the neurotoxic effects of NMDA antagonists most likely through agonist actions at 5-HT2 receptors.

Male C57BL/6J mice were provided I-deprenyl (at 0, 0.5 mg/kg or 1.0 mg/kg per day) in their drinking water beginning at 18 months of age. A battery of motor tests, including open-field, tightrope, rotorod, inclined screen, runwheel, and rotodrum tests, was administered before treatment and then 6 months later at 24 months of age. A subsample of mice was retested again at 27 months of age. An untreated group of 9-month-old mice served as young controls. Deprenyl treatment reduced striatal MAO-B activity by up to 60% after 6 months on treatment but had no significant effects on striatal catecholamine levels. No significant effects of deprenyl treatment were observed on body weight, fluid intake, or survival of the mice. Chronic deprenyl treatment also did not affect motor performance in any test, except rotodrum performance at 27 months of age, which was significantly better in the 1.0 mg/kg group treated group compared to controls. No age or deprenyl effects were observed with respect to cell counts in the substantia nigra. However, nigral cells containing lipofuscin increased with age, but this neurohistochemical parameter was also unaffected by deprenyl treatment.

Noradrenergic (NA) involvement in acquisition (AQ) and retention (RET) of a shock-motivated 14-unit T-maze after intraperitoneal (ip) administration of DSP4, a neurotoxin that depletes forebrain NA, was evaluated in 2 experiments using 3-month-old male F-344 rats. Depletion of cortical NA level in DSP4-treated rats was verified by neurochemical assay and by latency to postdecapitation clonus reflex. In Experiment 1, DSP4 (50 mg/kg ip) rats did not differ from saline-treated (SAL) rats on any measure of maze performance (errors, alternation errors, run time, shock duration, or shock frequency) during AQ (DSP4 2 weeks prior to testing) nor during a RET test 2-3 weeks later (DSP4 immediately after the last AQ trial or 1 week after AQ). In Experiment 2, DSP4 and scopolamine (SCOP), a cholinergic (ACh) antagonist, were administered in combination to test for an NA-ACh interaction. DSP4 (50 mg/kg ip 2 weeks prior to AQ) again had no effect on AQ performance nor did DSP4 interact with either dose of SCOP (0.25 or 0.5 mg/kg ip 30 min prior to AQ) to further impair performance. Similar to previous studies SCOP impaired all measures of maze performance except shock duration. These experiments provide further evidence for involvement of ACh systems in the learning of this task and in the age-related impairments previously observed, but they suggest that central NA systems may not be involved directly or interactively with ACh systems required for efficient performance in this maze.

Scopolamine was utilized to assess cholinergic muscarinic blockade on the performance of young (3 months) and aged (23 months) male F-344 rats in a 14-unit T-maze task. Prior to training, a portion of each age group received a gustatory neophobia test (percent consumption of a novel sucrose solution) to assess involvement of norepinephrine systems implicated in age-related impairments of rats in other memory tasks. All rats were pretrained in one-way active avoidance (1.0 mA) on 3 consecutive days. Rats meeting criterion (8/10 avoidances on last day) began maze training the next day consisting of 10 trials on 2 consecutive days. The task required the rat to negotiate each of 5 maze segments within 10 sec to avoid scrambled footshock (1.0 mA). Rats received an intraperitoneal injection of either scopolamine hydrochloride (0.5 mg/kg or 0.75 mg/kg) or saline vehicle 30 min prior to maze testing. Consistent with past reports, aged rats were more neophobic (i.e., consumed less sucrose) than were young rats, but the degree of neophobia was not significantly correlated with maze error performance in either age group. Also consistent with previous studies, aged rats were significantly impaired, compared to young counterparts, in all maze performance measures including errors, alternation errors, runtime, and shock frequency and duration. Significant scopolamine-induced deficits were observed in both age groups, but only in errors and alternation strategy. No age by drug interaction was manifested in any performance measure indicating that scopolamine impaired learning of young and aged rats equivalently.(ABSTRACT TRUNCATED AT 250 WORDS)

Young (3-months) and aged (24-months) male F-344 rats were pretrained in one-way active avoidance in a straight runway for 3 days. Then two 10-trial daily sessions were given in a 14-unit T-maze in which the response requirement was to negotiate each of 5 maze segments within 10 s to avoid footshock. One day or one week after acquisition, bilateral electrolytic lesions were made in the fimbria-fornix of young rats (1-day lesion or 1-week lesion). Corresponding sham operations were made for remaining young rats (1-day sham or 1-week sham). Aged animals did not receive any surgical treatment. One week after surgery, a 10-trial retention test was conducted to assess the lesion effects on retention and to manipulate the interval between acquisition and lesions. Aged animals were tested in the maze 1 week after acquisition. Results revealed that rats with fimbria-fornix lesions exhibited significant impairment compared to sham-operated groups on all retention performance measures including errors, runtime, number of shocks, duration of shock, and alternation errors. The number of errors and alternation errors of lesioned animals were still higher than those of sham-operated animals at the second half of the retention test, whereas other non-cognitive measures for lesioned animals recovered to control levels. The interval between acquisition training and lesions had no influence on retention performance. Although performance of aged rats during acquisition and retention trials was significantly worse than that of young controls and lesioned animals, a similar recovery pattern during retention testing was found for young rats with fimbria-fornix lesions and aged rats, i.e. both groups showed significant declines in non-cognitive measures with less decline in cognitive measures. These results suggest that the fimbria-fornix is partially involved in retention of 14-unit T-maze performance and that the age-related retention deficit observed in this task may be related to impaired transmission through this pathway.

To follow up a previous report noting that scopolamine impaired acquisition performance of young rats in a shock-motivated 14-unit T-maze, the present study assessed the effects of muscarinic antagonism on retention aspects of the same task. The broader objective was to further the investigation of possible defects in cholinergic neurotransmission that might underlie the age-related impairments previously observed in this task. Young (3-month) male F-344 rats were given preliminary training to criterion in one-way active avoidance in a straight runway. Then on the first day of complex maze training, each rat received 5 acquisition (AQ) trials followed by a second 10-trial retention (RET) session conducted the following day. Subjects were assigned to one of eight groups receiving an intraperitoneal injection of either scopolamine hydrochloride (1.0 mg/kg) or saline as follows: (a) 30 min prior to training on the first day (PRE-AQ); (b) 30 min prior to training on both the first and second day (PRE-AQ-RET); (c) immediately after completing the trial on the first day (POST-AQ); (d) 30 min prior to testing on the second day (PRE-RET). Dependent measures included errors, alternation errors, run time, number of shocks, and total shock received. On the first day of maze training, all performance measures except for alternation errors were significantly higher for the two acquisition groups (PRE-AQ and PRE-AQ-RET) compared to all other groups which did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)