Ileal transposition: A non-restrictive bariatric surgical procedure that reduces body fat and increases ingestion-related energy expenditure.

BACKGROUND: Ileal Transposition (IT) was developed as a model to study body weight reduction without the restrictive or malabsorptive aspects of other bariatric surgeries, but the exact mechanisms of the alterations in body weight after IT are not completely understood. OBJECTIVE: To provide a detailed description of the surgical procedure of IT, and describe its effect on energy balance parameters. METHODS: Adult male Lewis rats underwent either IT (IT+) or sham (IT-) surgery. Following surgery body weight and energy intake were monitored. After attaining weight stability (> 30 days), energy expenditure and its components were assessed using indirect calorimetry at a day of fasting, limited intake, and ad libitum intake. At the end of the study body composition analysis was performed. RESULTS: IT+ resulted in transiently reduced energy intake, increased ingestion-related energy expenditure (IEE) and decreased body and adipose tissue weight when compared to IT-. At weight stability, neither energy budget (i.e., energy intake - energy expenditure), nor energy efficiency was different in IT+ rats compared to IT-. CONCLUSION: Our data show that the primary cause of weight reduction following IT+ is a transient reduction in energy intake. If the increased IEE is related to a higher level of satiety, compensatory feeding to bridge body weight difference between IT+ and IT- rats is less likely to occur.

Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats.

Exercise can exert beneficial effects on cognitive functions of older subjects and it can also play an important role in the prevention of neurodegenerative diseases. At the same time it is perceivable that limited information is available on the nature of molecular pathways supporting the antioxidant effects of exercise in the brain. In this study 12-month old, middle-aged female Wistar rats were subjected to daily moderate intensity exercise on a rodent treadmill for a period of 15weeks which covered the early aging period unmasking already some aging-related molecular disturbances. The levels of reactive oxygen species (ROS), the amount of protein carbonyls, the levels of antioxidant intracellular enzymes superoxide dismutases (SOD-1, SOD-2) and glutathione peroxidase (GPx) were determined in the hippocampus. In addition, to identify the molecular pathways that may be involved in ROS metabolism and mitochondrial biogenesis, the activation of 5'-AMP-activated protein kinase (AMPK), the protein level of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (mtTFA) were measured. Our results revealed a lower level of ROS associated with a reduced amount of protein carbonyls in the hippocampus of physically trained rats compared to sedentary controls. Furthermore, exercise induced an up-regulation of SOD-1 and GPx enzymes, p-AMPK and PGC-1α, that can be related to an improved redox balance in the hippocampus. These results suggest that long-term physical exercise can comprises antioxidant properties and by this way protect neurons against oxidative stress at the early stage of aging.

Perinatal polyunstaurated fatty acids supplementation causes alterations in fuel homeostasis in adult male rats but does not offer resistance against STZ-induced diabetes.

Maternal factors can have major imprinting effects on homeostatic mechanisms in the developing fetus and newborn. Here we studied whether supplemented perinatal polyunsaturated fatty acids (PUFAs) influence energy balance and fuel homeostasis later in life. Between day 10 after conception and day 10 after delivery, female rats were subjected to chow enriched with 10% fish-oil (FO-rich). Fish oil contains high concentrations of n-3 biosynthesis endpoint products, which may have caused the increased membrane phospholipid incorporation (particularly derived from the long-chain 20 +:n-3 PUFAs) in 10-day old pup brains. Adult male offspring of FO-rich fed rats had reduced body weight (- 20%) at 3 months, and had lower levels of plasma leptin (- 54%), insulin (- 41%), triglycerides (- 65%), and lactate (- 46%) than controls. All differences between groups were lost 48 h after streptozotocin (STZ) treatment. At 4.5 months of age, body weights of FO-rich were still lower (- 6%) than controls, but were associated with increased food intake, and increased insulin sensitivity (following intraperitoneal injection) to lower blood glucose levels relative to controls. We concluded that perinatal FO supplementation has lasting effects on body weight homeostasis and fuel metabolism in male offspring, but does not offer resistance against STZ-induced diabetes.

Behavioral traits are affected by selective breeding for increased wheel-running behavior in mice.

Voluntary physical activity may be related to personality traits. Here, we investigated these relations in two mouse lines selectively bred for high voluntary wheel-running behavior and in one non-selected control line. Selection lines were more explorative and "information gathering" in the open-field test, either with increased upright positions or horizontal locomotion toward the middle ring. Furthermore, one of the selection lines had an increased risk-taking behavior relative to the control line in approaching a novel object placed in the center of the open field. However, anxiety behavior was increased in selection lines during the plus-maze test. Maze learning was not statistically different among lines, but routine behavior was increased in both selection lines when the maze exit after 2 days of testing was displaced. Specifically, in the displaced maze, selected mice traveled more frequently to the old, habituated exit, bypassing the new exit attached to their home cage. Although the generality of the results would need to be confirmed in future studies including all eight lines in the selection experiment, the increased routine and exploratory behavior (at least in the lines used in the present study) may be adaptive to sustain high activity levels.

Effects of selective breeding for increased wheel-running behavior on circadian timing of substrate oxidation and ingestive behavior.

Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running behavior, either when feeding a carbohydrate-rich/low-fat (LF) or a high-fat (HF) diet. Housed without wheels, selected mice, and in particular the females, exhibited higher cage activity than their non-selected controls during the dark phase and at the onset of the light phase, irrespective of diet. This was associated with increases in energy expenditure in both sexes of the selection line. In selected males, carbohydrate oxidation appeared to be increased compared to controls. In contrast, selected females had profound increases in fat oxidation above the levels in control females to cover the increased energy expenditure during the dark phase. This is remarkable in light of the finding that the selected mice, and in particular the females showed higher preference for the LF diet relative to controls. It is likely that hormonal and/or metabolic signals increase carbohydrate preference in the selected females, which may serve optimal maintenance of cellular metabolism in the presence of augmented fat oxidation.

Impact of repeated bouts of eccentric exercise on sarcolemma disruption in human skeletal muscle.

In animal models, unaccustomed eccentric exercise (EE) has been widely related to muscle fiber membrane (sarcolemma) damage. On the contrary, studies in humans reported that sarcolemma was not susceptible to damage following a single bout of EE. We hypothesized that the single bout of EE used by those studies was not sufficient to induce sarcolemma damage, in humans. In this study we examined muscle biopsies from untrained males who either performed six sets of 15 reps of maximum voluntary eccentric contractions (n=9), for six consecutive days, or served as control-group (n=6). Blood and biopsy samples were obtained one week prior to exercise, immediately after bout 3, and 24h after the last training session. In addition to standard haematoxylin-eosin staining, all biopsies were stained immunohistochemically using antibodies specific for fibronectin and desmin antigens. In the exercise-group, no biopsies taken at pre-exercise or post-exercise level showed evidence of sarcolemma damage as stained by anti-fibronectin antibody in eight of nine subjects. Serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities increased significantly throughout the study despite the lack of sarcolemma damage.We suggest that in humans, repeated bouts of EE do not cause gross sarcolemma damage in the mid-belly of Vastus Lateralis.

Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats.

AIMS: Previous studies on the therapeutic time window for intravascular administration of bone marrow stem cells (BMSCs) after stroke have shown that early intervention (from 3 h after onset) in the middle cerebral artery occlusion (MCAO) rat model is the most effective approach to reduce ischaemic lesion size. We have confirmed these observations but noticed that 2 weeks after transplantation, almost none of the grafted BMSCs could be detected in or around the lesion. The present experiments aimed to assess the fate and kinetics of intravascularly injected BMSCs shortly after administration in correlation to the development of the ischaemic lesion after MCAO. METHODS: We administered a syngeneic suspension of complete (haematopoietic and mesenchymal) BMSCs via the carotid artery to rats at 2 h after MCAO onset. We examined the distribution and tissue location of BMSCs within the first 24 h after arterial administration by perfusion-fixating rats and performing immunohistochemical analysis at different time points. RESULTS: The vast majority (>95%) of BMSCs appeared to become trapped in the spleen shortly after injection. Six hours after implantation, together with the appearance of activated microglia, the first BMSCs could be detected in and around the lesion; their number gradually increased during the first 12 h after implantation but started to decrease at 24 h. The implanted BMSCs were surrounded by activated and phagocytotic microglia. CONCLUSION: Our results show that ischaemic lesion size reduction can already be achieved by the early transient presence at the lesion site of intravascularly implanted BMSCs, possibly mediated via activated microglia.

The effect of exercise and oxidant-antioxidant intervention on the levels of neurotrophins and free radicals in spinal cord of rats.

STUDY DESIGN: This study was designed to investigate the effects of oxidant and antioxidant treatment, as well as regular exercise, on neurotrophin levels in the spinal cord of rats. OBJECTIVES: Reactive oxygen species (ROS) play a role in neurodegenerative diseases, but ROS at moderate levels could stimulate biochemical processes through redox-sensitive transcription. METHODS: Exercised or sedentary animals were injected subcutaneously with hydrogen peroxide (H(2)O(2)), N-tert butyl-alpha-phenyl nitrone (PBN) or saline for the last 2 weeks of a 10-week experimental period to challenge redox balance. Free radical (FR) concentration was evaluated in the spinal cord by electron spin resonance, protein carbonyls, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) levels and the mRNA expression of BDNF receptor and tyrosine kinase receptor B (TrKB). SETTING: Research Institute of Sport Science, Semmelweis University, Budapest, Hungary. RESULTS: Exercise or PBN decreased the concentration of FR, whereas the carbonyl content did not change. BDNF was significantly decreased in exercised sham and sedentary PBN-treated groups, and its content correlated with the level of FR. GDNF was significantly increased in sedentary H(2)O(2)-treated groups. No differences were observed in TrkB mRNA expression among groups. CONCLUSIONS: Results suggest that regular exercise alone and PBN in sedentary animals can successfully decrease FR levels in the spinal cord. Redox alteration seems to affect the levels of GDNF and BDNF, which might have clinical consequences, as neurotrophins play an important role in cellular resistance and regeneration.

Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons.

Vinpocetine (ethyl apovincaminate), a synthetic derivative of the Vinca minor alkaloid vincamine, is widely used for the treatment of cerebrovascular-related diseases. One of the proposed mechanisms underlying its action is to protect against the cytotoxic effects of glutamate overexposure. Glutamate excitotoxicity leads to the disregulation of mitochondrial function and neuronal metabolism. As Vinpocetine has a binding affinity to the peripheral-type benzodiazepine receptor (PBR) involved in the mitochondrial transition pore complex, we investigated whether neuroprotection can be at least partially due to Vinpocetine's effects on PBRs. Neuroprotective effects of PK11195 and Ro5-4864, two drugs with selective and high affinity to PBR, were compared to Vinpocetine in glutamate excitotoxicity assays on primary cortical neuronal cultures. Vinpocetine exerted a neuroprotective action in a 1-50microM concentration range while PK11195 and Ro5-4864 were only slightly neuroprotective, especially in high (>25microM) concentrations. Combined pretreatment of neuronal cultures with Vinpocetine and PK11195 or Ro5-4864 showed increased neuroprotection in a dose-dependent manner, indicating that the different drugs may have different targets. To test this hypothesis, mitochondrial membrane potential (MMP) of cultured neurons was measured by flow cytometry. 25microM Vinpocetine reduced the decrease of mitochondrial inner membrane potential induced by glutamate exposure, but Ro5-4864 in itself was found to be more potent to block glutamate-evoked changes in MMP. Combination of Ro5-4864 and Vinpocetine treatment was found to be even more effective. In summary, the present results indicate that the neuroprotective action of vinpocetine in culture can not be explained by its effect on neuronal PBRs alone and that additional drug targets are involved.

Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity.

OBJECTIVE: Increased dietary fat intake is a precipitating factor for the development of obesity and associated metabolic disturbances. Physically active individuals generally have a reduced risk of developing these unhealthy states, but the underlying mechanisms are poorly understood. In the present study, we investigated the effects of feeding a high-fat diet (HFD) on obesity development and fuel homeostasis in male and female mice with a trait for increased physical activity and in their controls. METHODS: Male and female mice selectively bred for a high level of wheel running behavior over 30 generations and nonselected controls (background strain Hsd:ICR) were maintained on a standard lab chow high-carbohydrate diet (HCD) or on an HFD (60% fat). Food intake, body weight, indirect calorimetry parameters, spontaneous locomotor activity and several hormones relevant to metabolism and energy balance were measured. RESULTS: On HFD, mice reduced food intake and increased body fat mass and plasma leptin levels, with the notable exception of the selected females, which increased their ingested calories without any effects on body mass or plasma leptin levels. In addition, they had an elevated daily energy expenditure (DEE), increased spontaneous cage activity ( approximately 700% relative to controls) and higher resting metabolic rate (RMR) on the HFD compared with feeding the HCD. The selected males also had a higher DEE compared with controls, but no interaction with diet was observed. On HCD, adiponectin levels were higher in selected male, but not female, mice relative to controls. A marked increase in the level of plasma adiponectin was observed on the HFD in selected females, an effect of diet that was not observed in selected males. CONCLUSION: Genetically based high locomotor activity renders female, but not male, mice resistant to HFD-induced obesity by alterations in behavioral, endocrine and metabolic traits that facilitate fat utilization rather than limiting HFD intake.

Estrogen receptor alpha and beta immunoreactive neurons in normal adult and aged female rat hippocampus: a qualitative and quantitative study.

We have studied the distribution pattern and levels of expression of two estrogen receptor (ER) subtypes, ERalpha and ERbeta, in the normal adult (n = 10) and the aged (n = 10) female rat hippocampus with the objective to establish baseline data and the changes that occur during aging. Techniques including immunohistochemical localization, co-localization with double immunofluorescence and confocal microscopy, image analysis including neuronal counts/mm(2) area and measurements of optical density (OD) of immunoreactivity in immunoreactive neurons and Western blot analysis have been used. The results revealed ERalpha and ERbeta positive neurons in all subfields of the hippocampus with maximum presence in the stratum pyramidale of CA3. Some stained neurons in CA3 exhibited pyramidal neuron like morphological characteristics; such neurons were not found in CA1. All other immunoreactive neurons showed non-pyramidal neuron like morphological characteristics. Neuronal counts revealed a significant decrease in the number of immunoreactive neurons in CA3-CA1 of aged hippocampus. The percent decrease in counts of the immunoreactive neurons/mm(2) area in the aged rat (compared to the adult) was 78% for the ERalpha and 88% for the ERbeta (P < 0.001) in CA3. In CA1, it was 56% (P < 0.001) and 41% (P < 0.01) respectively. The OD of immunoreactivity was significantly decreased (P < 0.01) in CA3 but increased (P < 0.01) in the CA1 immunoreactive neurons. Western blot analysis also showed a significant decline (P < 0.01) in the levels of the ERalpha and ERbeta proteins in the aged hippocampus. Co-localization revealed that the two ER subtypes do co-exist in the same hippocampal neurons.

A review of the neuroprotective properties of the 5-HT1A receptor agonist repinotan HCl (BAYx3702) in ischemic stroke.

Repinotan HCl (repinotan, BAYx3702), a highly selective 5-HT1A receptor agonist with a good record of safety was found to have pronounced neuroprotective effects in experimental models that mimic various aspects of brain injury. Repinotan caused strong, dose-dependent infarct reductions in permanent middle cerebral artery occlusion, transient middle cerebral artery occlusion, and traumatic brain injury paradigms. The specific 5-HT1A receptor antagonist WAY 100635 blocked these effects, indicating that the neuroprotective properties of repinotan are mediated through the 5-HT1A receptor. The proposed neuroprotective mechanisms of repinotan are thought to be the result of neuronal hyperpolarization via the activation of G protein-coupled inwardly rectifying K+ channels upon binding to both pre- and post-synaptic 5-HT1A receptors. Hyperpolarization results in inhibition of neuron firing and reduction of glutamate release. These mechanisms, leading to protection of neurons against overexcitation, could explain the neuroprotective efficacy of repinotan per se, but not necessarily the efficacy by delayed administration. The therapeutic time window of repinotan appeared to be at least 5 h in in vivo animal models, but may be even longer at higher doses of the drug. Experimental studies indicate that repinotan affects various mechanisms involved in the pathogenesis of brain injury. In addition to the direct effect of repinotan on neuronal hyperpolarization and suppression of glutamate release this compound affects the death-inhibiting protein Bcl-2, serotonergic glial growth factor S-100beta and Nerve Growth Factor. It also suppresses the activity of caspase-3 through MAPK and PKCalpha; this effect may contribute to its neuroprotective efficacy. The dose- and time-dependent neuroprotective efficacy of repinotan indicates that the drug is a promising candidate for prevention of secondary brain damage in brain-injured patients suffering from acute ischemic stroke. Unfortunately, however, the first, randomized, double blind, placebo-controlled clinical trial did not demonstrate the efficacy of repinotan in acute ischemic stroke.

Neuroprotective effect of developmental docosahexaenoic acid supplement against excitotoxic brain damage in infant rats.

Long-chain polyunsaturated fatty acid (LC-PUFA) composition of neural membranes is a key factor for brain development, in chemical communication of neurons and probably also their survival in response to injury. Viability of cholinergic neurons was tested during brain development following dietary supplementation of fish oil LC-PUFAs (docosahexaenoic acid [DHA], eicosapentaenoic acid, arachidonic acid) in the food of mother rats. Excitotoxic injury was introduced by N-methyl-D,L-aspartate (NMDA) injection into the cholinergic nucleus basalis magnocellularis of 14-day-old rats. The degree of loss of cholinergic cell bodies, and the extend of axonal and dendritic disintegration were measured following immunocytochemical staining of cell bodies and dendrites for choline acetyltransferase and p75 low-affinity neurotrophin receptor and by histochemical staining of acetylcholinesterase-positive fibres in the parietal neocortex. The impact of different feeding regimens on fatty acid composition of neural membrane phospholipids was also assayed at 12 days of age. Supplementation of LC-PUFAs resulted in a resistance against NMDA-induced excitotoxic degeneration of cholinergic neurones in the infant rats. More cholinergic cells survived, the dendritic involution of surviving neurons in the penumbra region decreased, and the degeneration of axons at the superficial layers of parietal neocortex also attenuated after supplementing LC-PUFAs. A marked increment in DHA content in all types of phospholipids was obtained in the forebrain neuronal membrane fraction of supplemented rats. It is concluded that fish oil LC-PUFAs, first of all DHA, is responsible for the neuroprotective action on developing cholinergic neurons against glutamate cytotoxicity.

Chronic excess of corticosterone increases serotonergic fibre degeneration in aged rats.

Evidence is presented for the potentiating role of corticosterone on axonal degeneration of serotonergic neurones during ageing. Aged rats, 24 months old, were implanted subcutaneously with 2 x 100 mg pellets of corticosterone. Serotonergic and cholinergic (ChAT- and NADPHd-positive) fibre degenerations in the anteroventral thalamic nucleus (AVT) were measured 2 months after corticosterone implantation. Numbers of immunoreactive serotonergic raphe and mesolimbic cholinergic neurones were also quantified. Basal plasma corticosterone and adrenocorticotropin (ACTH) concentrations were assayed at 2, 4, 6, and 8 weeks after implantation in the plasma and at 1, 2, 4 and 6 weeks in urine. The degree of serotonergic fibre aberrations in the AVT increased significantly after corticosterone exposure, while that of ChAT-positive and NADPHd-stained axon aberrations showed a modest but nonsignificant increase. A positive correlation between the magnitudes of serotonergic and cholinergic fibre aberrations appeared in the AVT, but only in the corticosterone-treated rats. The number of serotonin immunopositive neurones in the raphe nuclei after corticosterone decreased marginally, while that of mesopontine ChAT-positive neurones was not influenced. Measurements of basal plasma corticosterone and ACTH, as well as urine corticosterone, revealed that the steroid implantation increased the plasma corticosterone level for at least 4 weeks and decreased ACTH level for at least 6 weeks. By the week 8, the pituitary-adrenal function was apparently restored. However, at sacrifice, both the weight of adrenal glands and that of thymus remained reduced, indicating the long-lasting effects of corticosterone on target tissues. It is concluded that the raphe serotonergic neurones and their projecting fibres are sensitive to corticosterone excess in aged rats and become more vulnerable to degeneration processes than under normal ageing conditions. Cholinergic neurones of brainstem origin, which also express massive NADPHd activity, are more resistant against corticosterone, but their axon degeneration correlates to serotonergic fibre degeneration.

Cutaneous lymphatic amyloid deposits in "Hungarian-type" familial transthyretin amyloidosis: a case report.

Multiple transthyretin (TTR) mutations have recently been identified and implicated in the development of familial systemic amyloidoses, but early diagnosis of these disorders is still largely unresolved. We investigated the presence and tissue distribution of TTR-derived amyloid in skin biopsies of a 59-year-old woman carrying the "Hungarian-type" mutation of TTR (Asp18Gly). Clinical symptoms involved severe central nervous system dysfunction without signs of polyneuropathy, also referred to as the "central form" of TTR-related systemic amyloidosis. Skin biopsy was also evaluated as a tool in order to diagnose this type of TTR amyloidosis. Biopsy samples were collected from the infra-axillary region. Light microscopy using Congo red and polarized light was used to diagnose amyloid deposits. Subsequently, electron microscopic analysis was performed to correlate the amyloid deposits with vicinal dermal structures. The amyloid class was determined by means of immunocytochemistry. TTR amyloid was primarily localized to lymphatic microvessels in the present case, whereas arterioles were devoid of TTR amyloid deposits. In addition, the well-known association of TTR amyloid with neural structures along the erector pilorum and around the sebaceous and serosal (sweat) glands was also evident. Electron microscopic analysis of amyloid deposits revealed characteristic amyloid fibrils that were irregular in shape, and exhibited a heterogeneous density and a random deposition pattern. Immunocytochemistry confirmed the cutaneous accumulation of TTR amyloid. In conclusion, amyloid deposits were abundantly present in the skin of a patient with "Hungarian-type" TTR amyloidosis; skin biopsy seems to be appropriate for the diagnosis of this disorder. We showed that besides the erector pilorum, sweat glands and nerve terminals, lymphatic microvessels are also severely infiltrated by TTR amyloid. Whether these pathological alterations can exclusively be found in "Hungarian-type" TTR amyloidosis should still be investigated. If such changes are not specific for the Asp18Gly mutation, they may be considered as diagnostic markers for "central" TTR amyloid disorders.

Neonatal maternal deprivation modifies feeding in response to pharmacological and behavioural factors in adult rats.

Neonatal maternal deprivation permanently modifies the hypothalamo-pituitary-adrenal (HPA) axis and other neurobiological and behavioural parameters in rats. The HPA axis plays a central role in the control of feeding, and participates in the anorexigenic action of dexfenfluramine and restraint stress, and in the orexigenic action of a cafeteria diet. Therefore, we investigated whether maternal deprivation modifies feeding responses to these factors. Experimental pups were separated for 24h from the mother 5 or 14 days after birth. The anorexigenic response to both dexfenfluramine and restraint stress was increased, and body weight as well as subcutaneous adipose tissue gain induced by cafeteria diet was higher in early deprived adult rats. However, these effects were dependent on the time of maternal deprivation. According to our predictions, the feeding response of maternally deprived rats to anorexigenic and orexigenic agents was altered, which is probably partly due to an altered HPA function, but the participation of the serotonergic, the opioid and/or the dopaminergic system cannot be ruled out. Additional studies are needed to detail precisely the neurobiological substrates of modified feeding behaviour of maternally deprived animals. This early stress paradigm altering feeding behaviour could become an interesting model for research into human eating disorders.

Oral post-lesion administration of 5-HT(1A) receptor agonist repinotan hydrochloride (BAY x 3702) attenuates NMDA-induced delayed neuronal death in rat magnocellular nucleus basalis.

Recent evidence indicates that stimulation of postsynaptic 5-HT(1A) receptors abates excitotoxic neuronal death. Here we investigated whether oral post-lesion administration of the 5-HT(1A) receptor agonist (-)-(R)-2-[4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]butyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide monohydrochloride (Repinotan HCl) attenuates N-methyl-D-aspartate (NMDA) excitotoxicity (60 nmol/microl) in the rat magnocellular nucleus basalis. Repinotan HCl (1 mg/kg) was administered from day 1, 2, 3, or 6 post-surgery twice daily for five consecutive days. This delayed drug administration protocol was employed to investigate the initiation period during which 5-HT(1A) receptor agonists may significantly influence ongoing neurodegeneration processes. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 1 mg/kg) served as reference compound. Twenty-four hours after drug delivery a small open-field test, while on day 14 post-surgery a passive avoidance test was performed. Effects of Repinotan HCl treatment on the survival of cholinergic magnocellular nucleus basalis neurons and their cortical projections were determined by quantitative acetylcholinesterase (AChE) and choline-acetyltransferase (ChAT) histochemistry. Moreover, AChE and ChAT activities were biochemically measured both in the cerebral cortex and in the magnocellular nucleus basalis. Repinotan HCl treatment markedly increased spontaneous activities in the small open-field at any time-point investigated. Improved memory performance was only demonstrated when Repinotan HCl was administered from day 1 post-lesion on wards. Repinotan HCl treatment from day 2 and 3 post-lesion on markedly attenuated both histochemical and neurochemical characteristics of NMDA excitotoxicity on cholinergic magnocellular nucleus basalis neurons and on their cortical projections. Whereas the neuroprotective profile of Repinotan HCl was superior to that of 8-OH-DPAT, oral administration of both 5-HT(1A) receptor agonists yielded largely equivalent behavioral recovery after NMDA infusion in the magnocellular nucleus basalis. In conclusion, the present data indicate the potent neuroprotective action of the 5-HT(1A) receptor agonist Repinotan HCl with a peak efficacy of delayed (2-3 day) post-lesion drug treatment in vivo. Post-lesion treatment with 5-HT(1A) receptor agonists may therefore be of significance in the intervention of neuronal damage associated with acute excitotoxic conditions.

Postnatal maternal deprivation produces long-lasting modifications of the stress response, feeding and stress-related behaviour in the rat.

The hypothalamo-pituitary-adrenal (HPA) axis plays a central role both in the regulation of the stress response, and in the control of feeding behaviour. Sensitivity of the HPA axis to respond to stress varies both during ontogeny and between individuals, and can be altered by neonatal events. The aim of our experiments was to determine whether early events that affect the HPA axis could also induce persistent modifications in food intake (quantitatively and qualitatively), as well as alterations of anxiety-related behaviour. Twenty-four-hour maternal deprivation was introduced at two different periods of HPA maturation, on day 5 (DEP5) or day 14 (DEP14) after birth. Sequential measurements of plasma levels of adrenocorticotropin hormone (ACTH) and corticosterone showed that this deprivation altered the HPA axis of adults; the response to restraint stress was prolonged in DEP5 and a higher ACTH peak appeared in DEP14. The neonatal stress also produced long-lasting modifications of rat behaviour, as DEP14 adults became more anxious. Standard food intake decreased in both groups of deprived rats. Diet preferences also changed, as carbohydrate intake decreased in DEP5 rats. Corticosteroid receptor binding did not vary in the hippocampus of the deprived rats. The modifications of the stress response and the behaviour parameters could be due to the alteration of corticosteroid receptors in the hypothalamic paraventricular nucleus and/or corticotropin-releasing hormone or vasopressin function, but these parameters have yet to be determined. This early stress paradigm altering feeding behaviour could become an interesting model for research into human eating disorders.

Single bout of exercise eliminates the immobilization-induced oxidative stress in rat brain.

We were interested in the effects of immobilization (IM), a single bout of exercise (E) and immobilization followed by exercise (EIM) on memory and oxidative damage of macromolecules in hippocampus of rat brain. Eight hours of IM resulted in impairment of passive avoidance test (memory retrieval deficit) and increased latency to start locomotion in an open-field test. Two hours of swimming did not significantly alter the memory retrieval deficit and latency, while the EIM group had longer latency and similar memory than control and E groups. The oxidative damage of lipids, proteins and nuclear DNA increased significantly in IM group and no increase was observed in E and EIM animals. The activity of proteasome was not altered in any groups. The activity of glutamine synthetase (GS) was decreased in IM group (P < 0.05), this down regulation was not observed in E and EIM groups. These data suggest that oxidative damage of macromolecules is associated with impaired cognitive function. Single bout of exercise after immobilization eliminates the oxidative damage of macromolecules and normalizes memory function, probably by its ability to restore the activity level of GS and eliminate the consequences of immobilization-induced prolonged efflux of glutamate.

Temporal and spatial dynamics of corticosteroid receptor down-regulation in rat brain following social defeat.

The experiments explored the nature and time course of changes in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) binding in homogenates of various brain regions and pituitary of male Wistar rats following social defeat stress. One week after defeat, the binding capacity of GRs was decreased in the hippocampus and the hypothalamus while no changes were observed in the parietal cortex and the pituitary. The number of MRs remained at the same level as in undefeated rats. Three weeks postdefeat, the initially down-regulated GR returned to baseline level in the hippocampus and the hypothalamus. However, GR binding was now decreased in the parietal cortex. Severe down-regulation of MRs was detected in the hippocampal and septal tissue. The results show that brief but intense stress like social defeat induces a long-lasting down-regulation of corticosteroid receptors and that the temporal dynamics of these changes are not only differential for GRs and MRs but also for brain sites.