Biomedical subjects

S A Farr

Publications and source records attributed to S A Farr.

At least 19 recordsLinked to original sources

PubMed2006

Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM).

Accumulation of toxic amyloid-beta (Abeta)-peptide is suggested to cause oxidative stress in Alzheimer's disease (AD) brain, and decrease the content of polyunsaturated fatty acids (PUFA) in neuronal membrane lipids. The senescence accelerated prone mice (SAMP8) have age-related increases in the level of hippocampal Abeta-peptide, learning and memory deficits, and a shorter lifespan than their controls. The effects of age-related oxidative damage on PUFA content in membrane phospholipids (PL), and alpha-tocopherol concentration were investigated in hippocampus and amygdala of 2-, 4-, 12-, and 18-month-old SAMP8 mice. In comparison to the younger SAMP8 mice, the hippocampus of the 12-month-old mice contained lower proportions of docosahexaenoic acid (DHA) in phosphatidylserine (PS) and phosphatidylinositol (PI), and higher proportions of arachidonic acid (AA) in PS. Their amygdala contained a lower proportion of AA in phosphatidylcholine (PC). In the hippocampus of the oldest age group, the proportions of DHA in PS, and AA in PC and PI were higher than in the younger age groups. At 2 months of age, the amygdala contained a higher concentration of alpha-tocopherol than the hippocampus, but this difference between the two brain regions was lost with aging. The oldest age group contained the highest concentration of alpha-tocopherol, indicating a protection against oxidative damage of PUFA in brain membrane phospholipids.

Age Factors↗

PubMed2004

Quantitative proteomics analysis of specific protein expression and oxidative modification in aged senescence-accelerated-prone 8 mice brain.

The senescence-accelerated mouse (SAM) is a murine model of accelerated senescence that was established using phenotypic selection. The SAMP series includes nine substrains, each of which exhibits characteristic disorders. SAMP8 is known to exhibit age-dependent learning and memory deficits. In our previous study, we reported that brains from 12-month-old SAMP8 have greater protein oxidation, as well as lipid peroxidation, compared with brains from 4-month-old SAMP8 mice. In order to investigate the relation between age-associated oxidative stress on specific protein oxidation and age-related learning and memory deficits in SAMP8, we used proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. We report here that in 12 month SAMP8 mice brains the expressions of neurofilament triplet L protein, lactate dehydrogenase 2 (LDH-2), heat shock protein 86, and alpha-spectrin are significantly decreased, while the expression of triosephosphate isomerase (TPI) is increased compared with 4-month-old SAMP8 brains. We also report that the specific protein carbonyl levels of LDH-2, dihydropyrimidinase-like protein 2, alpha-spectrin and creatine kinase, are significantly increased in the brain of 12-month-old SAMP8 mice when compared with the 4-month-old SAMP8 brain. These findings are discussed in reference to the effect of specific protein oxidation and changes of expression on potential mechanisms of abnormal alterations in metabolism and neurochemicals, as well as to the learning and memory deficits in aged SAMP8 mice.

Aging↗

PubMed2001

Delivery across the blood-brain barrier of antisense directed against amyloid beta: reversal of learning and memory deficits in mice overexpressing amyloid precursor protein.

Amyloid beta protein (Abeta) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Abeta, can be reversed with i.c.v. injections of an Abeta antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with (32)P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 +/- 0.39 microl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken up by each gram of brain (0.865 +/- 0.115%) being about 1/100 of the i.c.v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.

Alzheimer Disease↗

PubMed2001

Intravenous human interleukin-1alpha impairs memory processing in mice: dependence on blood-brain barrier transport into posterior division of the septum.

Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1alpha (hIL-1alpha; mIL-1alpha) are transported across the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1alpha to affect memory. Retention was impaired in a dose-dependent manner when hIL-1alpha was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1alpha was reversed by injecting a blocking antibody (Ab) specific for hIL-1alpha into the PDS. This shows that much of the memory impairment induced by hIL-1alpha depends on its ability to cross the BBB. Ab specific for mIL-1alpha was also effective in reversing memory impairment, showing that hIL-1alpha releases mIL-1alpha from endogenous stores. Whether the mIL-1alpha was released from peripheral stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL-1alpha affects memory by releasing mIL-1alpha from endogenous stores and by crossing the BBB to act at sites within the PDS.

Algorithms↗

PubMed2000

Permanent and temporary inactivation of the hippocampus impairs T-maze footshock avoidance acquisition and retention.

The hippocampus is widely recognized as playing an important role in learning and memory. Lesions of the hippocampus can disrupt spatial navigational learning and memory and injection of drugs into the hippocampus can affect both spatial navigational and nonspatial tasks. In the current studies we tested the effects of bilateral of electrolytic lesions and reversible inactivation of the hippocampus on acquisition and retention of T-maze footshock avoidance conditioning. Electrolytic lesions, which destroyed 31+/-0.04% of the hippocampus, significantly impaired acquisition and retention for T-maze footshock avoidance. No differences were found in motivation to avoid shock, open field activity, or foot shock sensitivity between lesion and control groups. Temporary inactivation of the hippocampus with lidocaine administered immediately before training disrupted acquisition and retention for T-maze footshock avoidance. Temporary hippocampal inactivation performed just prior to retention testing and post-training inactivation in mice trained to first avoidance had no effect on retention. However, temporary post-training inactivation in 'undertrained' (enough trials to remember 1 week later if treated with saline, but not allowed to make the avoidance response) mice impaired retention. The current findings indicate that the hippocampus plays an important role in learning and memory processing in the aversive T-maze paradigm.

Animals↗

PubMed2000

Identification of age-dependent changes in expression of senescence-accelerated mouse (SAMP8) hippocampal proteins by expression array analysis.

Aging is associated with extensive cognitive impairments, although the biochemical and physiological basis of these deficits are unknown. As the hippocampus plays a vital role in cognitive functions, we have selected this tissue to analyze changes in gene expression at two different ages. Array technology is utilized to explore how gene expression in hippocampus is affected by accelerated cognitive impairment in Senescence-Accelerated Mouse (SAM P8) strain. We show that the expression of genes associated with stress response and xenobiotic metabolism are strongly affected at a time when cognitive impairment occurs. Affected genes include those involved both in signaling and chaperone function. The effector and regulator family of chaperones, which play an important role in protein folding, and also the xenobiotic metabolizing enzymes that play crucial role in antioxidant systems, show significant changes in gene expression between 4 and 12 months.

Aging↗

PubMed2000

Estradiol potentiates acetylcholine and glutamate-mediated post-trial memory processing in the hippocampus.

There is increasing evidence that estrogen is involved in CNS activity, particularly memory. Several studies have suggested that estrogen improves memory by enhancing cholinergic and glutamatergic activity. In the present studies, we examined the effects of administration into the hippocampus of 17 beta-estradiol and estrone on retention of T-maze footshock avoidance in female ovariectomized mice. Both 17 beta-estradiol and estrone improved retention on an equimolar basis in a dose-dependent fashion. We then used the T-maze footshock paradigm to test whether a dose of 17 beta-estradiol ineffective as a single injection (subthreshold) could potentiate the effects of arecoline, a cholinergic agonist, or L-glutamate, a glutamatergic agonist, on retention. The dose of either arecoline or L-glutamate needed to improve retention was reduced at least ten-fold by the low dose of 17 beta-estradiol. These findings support the concept that estrogen improves memory by potentiating the activity of the cholinergic and glutamatergic systems.

Acetylcholine↗

PubMed2000

The effect of cholinergic, GABAergic, serotonergic, and glutamatergic receptor modulation on posttrial memory processing in the hippocampus.

Though the hippocampus is widely recognized as important in learning and memory, most of the evidence for this comes from animal lesion and human pathological studies. Due to the relatively small number of drugs that have been tested in the hippocampus for their ability to alter posttrial memory processing, there is a general impression that memory processing involves only a few neurotransmitters. We have evaluated the effects of cholinergic, GABAergic, serotonergic, and glutamatergic receptor agonists and antagonists for their ability to facilitate or impair retention. CD-1 mice received acute intrahippocampal drug infusion following footshock avoidance training in a T-maze. Retention was tested 1 week after training and drug administration. The results indicate that receptor agonists of acetylcholine and glutamate improved retention, while antagonists impaired retention. However, scopolamine did not impair retention, but M1 and M2 antagonists did. Receptor agonists of serotonin and GABA impaired retention, while antagonists improved retention. Drugs acting on 5-HT-1 and 5-HT-2 as well as GABA(A) and GABA(B) receptor subtypes did not differentially effect retention.

Animals↗

PubMed2000

Modulation of memory processing in the cingulate cortex of mice.

To evaluate the possible role of the cingulate cortex in memory processing for training using a noxious stimulus, we trained mice on foot shock avoidance in a T-maze. Cholinergic, GABAergic, serotonergic, and glutamatergic agonists and antagonists were administered into the cingulate cortex immediately after training. Retention for the foot shock avoidance training was tested 1 week later. The results indicate that muscarinic and nicotinic agonists improved retention, while antagonists impaired it. GABA and serotonin agonists impaired retention, while antagonists improved it. Drugs acting on GABA(A) and GABA(B) receptors had similar effects on retention, as did drugs acting on serotonin 1 and 2 receptor subtypes. Glutamate improved retention, and AP5, an antagonist of the excitatory amino acid site of the NMDA receptor, impaired retention. The cingulate cortex, like other parts of the limbic system, is involved in memory processing that occurs shortly after training.

Acetylcholine↗

PubMed2000

Site-directed antisense oligonucleotide decreases the expression of amyloid precursor protein and reverses deficits in learning and memory in aged SAMP8 mice.

beta amyloid protein (Abeta) is a 40-43 amino acid peptide derived from amyloid precursor protein (APP). Abeta has been implicated as a cause of Alzheimer's disease (AD). Mice with spontaneous or transgenic overexpression of APP show the histologic hallmarks of AD and have impairments in learning and memory. We tested whether antisense phosphorothiolated oligonucleotides (AO) directed at the Abeta region of the APP gene given with or without antibody directed at Abeta could reverse the elevated protein levels of APP and the behavioral impairments seen in SAMP8 mice, a strain which spontaneously overexpresses APP. We found that intracerebroventricular (ICV) administration of antibody with either of two AOs directed at the midregion of Abeta improved acquisition and retention in a footshock avoidance paradigm, whereas two AOs directed more toward the C-terminal, a random AO, and vehicle were without effect. Three injections of the more potent AO given without antibody reduced APP protein levels by 43-68% in the amygdala, septum, and hippocampus. These results show that AO directed at the Abeta region of APP can reduce APP levels in the brain and reverse deficits in learning and memory.

Age Factors↗

PubMed2000

Beta-amyloid precursor polypeptide in SAMP8 mice affects learning and memory.

Senescence accelerated (SAMP8 [P8]) mice develop age-related deficits in memory and learning. We show that increased expression of amyloid precursor protein (APP) and its mRNA in the hippocampus are also age-related. Immunocytochemical data suggest that a critical amount of APP expression may be needed to generate amyloid (Abeta) protein plaques in the hippocampus. Deficits in acquisition and retention test performance were alleviated by administration of antibody to Abeta protein into the cerebral ventricles. This reversal of cognitive deficits provides a link between increased expression of both APP and Abeta protein and learning and memory loss in these mice.

Age Factors↗

PubMed2000

Permeability of the blood-brain barrier to albumin and insulin in the young and aged SAMP8 mouse.

The decrease in the insulin cerebrospinal fluid/serum ratio seen in Alzheimer's disease has been suggested as a mechanism by which brain glucose utilization could be perturbed. Insulin is transported across the blood-brain barrier (BBB) by a system that is altered by pathophysiological events. We used SAMP8 mice, a strain that by 8-12 months of age develops severe deficits in learning and memory, to determine whether the insulin transporter or BBB integrity was altered with aging. BBB integrity was measured by injecting radioactive albumin intravenously, washing out the vascular space up to 17 hours later, and measuring brain/serum ratios. This very sensitive method found no increase in the permeability of the BBB to albumin in young and aged SAMP8 mice. This compares with previous studies in humans with Alzheimer's disease and in other colonies of SAMP8 mice that have found evidence for BBB disruption. For radioactively labeled insulin, we used multiple-time regression analysis to measure both the unidirectional influx rate (Ki) and the reversible binding to brain endothelium (Vi). A non-significant decrease in the transport rate for whole brain occurred in aged SAMP8 mice. Ki and Vi values significantly varied among brain regions and the Ki for the thalamus and the Vi for the cerebellum and thalamus were higher in aged mice. We conclude that alterations in BBB integrity or the activity of the BBB insulin transporter do not underlie the deficits in learning and memory seen in the aged SAMP8 mouse.

Aging↗

PubMed1999

Septo-hippocampal drug interactions in post-trial memory processing.

To determine if serotonin and GABA regulate post-trial memory processing of the cholinergic projection from the septum to the hippocampus, mice were trained on footshock avoidance in a T-maze. Immediately after training, drugs were injected into the septum, hippocampus or both. Retention was tested 1 week after training and drug administration. Ketanserin, a serotonin type 2 receptor antagonist at a dose of 0.5 ng, had no measurable effect on retention, but it reduced the dose of bicuculline, in the septum, or arecoline in the hippocampus that was needed to improve retention. DOI, a serotonin type 2 receptor agonist at a dose of 2.5 ng, had the opposite effect of increasing the doses of bicuculline and arecoline needed to improve retention. Bicuculline, a GABA(A) receptor antagonist at a dose of 0.1 pg, did not affect retention when injected alone into the septum, but it reduced the dose of arecoline needed to improve retention in the hippocampus. Muscimol, a GABA(A) receptor agonist at a dose of 5 ng, injected into the septum, increased the dose of arecoline needed to improve retention. The results of this study are compatible with models that propose that serotonin innervation from the median raphe drives GABA interneurons in the medial septum that synapse on cholinergic neurons projecting to the hippocampus.

Animals↗

PubMed1999

Effects of wheatgerm agglutinin and aging on the regional brain uptake of HIV-1GP120.

HIV-1 is associated with infection and altered functions of the CNS, especially in the elderly. Most studies indicate that HIV-1 is not evenly distributed throughout the CNS but is concentrated in deep brain nuclei. This study examined whether regional or age-related differences in the permeability of the blood-brain barrier to gp120, the viral coat of HIV-1, exist. The initial concentration of gp120 in 10 brain regions correlated with vascular content in young and old mice. Susceptibility to wheatgerm agglutinin (WGA)-induced uptake of gp120, which relates to endothelial cell internalization, varied regionally, with no induction of uptake into the striatum or hypothalamus but with large increases in the cerebellum, cortex, and midbrain. Transport across the BBB, as measured by the unidirectional influx rate (Ki), also varied regionally with the hypothalamus, hippocampus, and pons-medulla showing the highest values for Ki and the striatum the lowest. These regional variations in the permeability of the BBB to gp120 could contribute to the inhomogeneous distribution of HIV-1 within the CNS whereas the failure to see differences with aging suggests other causes underlie the susceptibility of the elderly to the CNS manifestations of AIDS.

Aging↗

PubMed1999

Leptin and neuropeptide Y (NPY) modulate nitric oxide synthase: further evidence for a role of nitric oxide in feeding.

Recent studies have suggested a role for nitric oxide in the regulation of food intake. Neuropeptide Y (NPY) is one of the most potent orexigenic agents. Chronic administration of leptin decreases food intake. This study examined the effects of NPY and leptin on nitric oxide synthase (NOS) in the hypothalamus. Previously it has been demonstrated that obese (ob/ob) mice have elevated NOS levels in the hypothalamus. In this study we demonstrated that the administration of leptin (6 microg/day) subcutaneously (SC) for 3 days decreased body weight (P < 0.001) and food intake P < 0.001) in obese (ob/ob) mice as expected. In addition, leptin decreased NOS in the hypothalamus nu 37% (P < 0.01) and in brown adipose tissue by 69% (P < 0.01) but not in white adipose tissue. NPY was administered intracerebroventricularly to CD-1 mice at doses of 0.25 and 0.50 microg. Mice were sacrificed 15 min after injection and NOS was measured in their hypothalami. NPY at the lower dose increased NOS in the hypothalamus by 147%. These results, taken together, with previously published studies support the concept that nitric oxide may play a role as a mediator of the effects of NPY and leptin on food intake. The alterations of NOS in brown adipose tissue following leptin administration could result in changes in blood flow or metabolism in the brown fat.

Adipose Tissue↗

PubMed1999

Peripheral steroid sulfatase inhibition potentiates improvement of memory retention for hippocampally administered dehydroepiandrosterone sulfate but not pregnenolone sulfate.

Dehydroepiandrosterone sulfate (DHEAS) improves memory retention when administered peripherally. Estrone-3-O-sulfamate (EMATE), a steroid sulfatase inhibitor, potentiates the effect of DHEAS on memory retention such that lower doses of DHEAS improve memory retention. It is not clear if this effect is mediated by both compounds entering the central nervous system. In the current studies, mice were trained to avoid footshock in a T-maze and memory retention was tested 1 week later. DHEAS, injected into the hippocampus after training, improved memory retention in a dose-dependent manner. In previous studies, pregnenolone sulfate (PREGS) improved memory retention when injected into the hippocampus. EMATE, administered peripherally, potentiated the effect of centrally administered DHEAS on memory retention. However, EMATE did not potentiate the effect of centrally administered PREGS. It was concluded that EMATE, acting peripherally, increased plasma levels of DHEAS which entered the brain and added to the effect of centrally administered DHEAS. The failure of EMATE to potentiate PREGS is discussed.

Animals↗

PubMed1998

Age-related changes in septal serotonergic, GABAergic and glutamatergic facilitation of retention in SAMP8 mice.

SAMP8/TaJf(P8) mouse strain has an inherited age-related impairment of learning and memory with its onset relatively early in its lifespan. Previously, it was reported that cholinergic and glutamatergic drugs injected into the hippocampus after behavioral training showed considerable shifts in the dose that improved retention in mice at 12 compared to 4 months of age. Cholinergic neurons in the septum supply most of the acetylcholine released in the hippocampus. In the present study, we determined if altered functional status of neurotransmission in the septum might account for the decrease in cholinergic and glutamatergic activity in the hippocampus of older SAMP8 mice. After training on footshock avoidance, P8 mice received a drug injection into the septum. Retention was tested 1 week later. The results indicate that bicuculline, GABA-A, and saclofen, GABA-B, receptor antagonist had to be injected at a higher dose in 12- than in 4-month-old mice to improve retention. The serotonergic antagonists, ketanserin and methiothepin, both showed dose response shifts such that less drug was needed to improve retention in 12- as compared to 4-month-old mice. It required four times more L-glutamate to improve retention in 12- than in 4-month-old mice. Agonists for acetylcholine, dopamine and norepinephrine receptors or an opiate antagonist required little or no change in the dose needed to improve retention in older P8 mice. SAMP8 mice may show an age-related impairment of septohippocampal functioning.

Aging↗

PubMed1998

The pharmacology of post-trial memory processing in septum.

The septum is recognized as important in learning and memory, but relatively little is known about the role of specific neurotransmitter receptors in memory processing in the septum. We evaluated the role of the classical neurotransmitters in mice that were prepared for intraseptal microinfusion of drug solution after footshock avoidance training in T-maze. Retention for the footshock training was determined 1 week after training and drug administration. The results indicated that receptor agonists of dopamine, norepinephrine, glutamate and acetylcholine improved retention, while the antagonists impaired retention. Receptor agonists of serotonin, gamma-amino butyric acid (GABA) and opioids impaired retention, while antagonists improved retention.

Acetylcholine↗