Interleukin-1ß signaling in fenestrated capillaries is sufficient to trigger sickness responses in mice.

BACKGROUND: The physiological and behavioral symptoms of sickness, including fever, anorexia, behavioral depression, and weight loss can be both beneficial and detrimental. These sickness responses are triggered by pro-inflammatory cytokines acting on cells within the brain. Previous research demonstrates that the febrile response to peripheral insults depends upon prostaglandin production by vascular endothelial cells, but the mechanisms and specific cell type(s) responsible for other sickness responses remain unknown. The purpose of the present study was to identify which cells within the brain are required for sickness responses triggered by central nervous system inflammation. METHODS: Intracerebroventricular (ICV) administration of 10 ng of the potent pro-inflammatory cytokine interleukin-1ß (IL-1ß) was used as an experimental model of central nervous system cytokine production. We examined which cells respond to IL-1ß in vivo via fluorescent immunohistochemistry. Using multiple transgenic mouse lines expressing Cre recombinase under the control of cell-specific promoters, we eliminated IL-1ß signaling from different populations of cells. Food consumption, body weight, movement, and temperature were recorded in adult male mice and analyzed by two-factor ANOVA to determine where IL-1ß signaling is essential for sickness responses. RESULTS: Endothelial cells, microglia, ependymal cells, and astrocytes exhibit nuclear translocation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in response to IL-1ß. Interfering with IL-1ß signaling in microglia, endothelial cells within the parenchyma of the brain, or both did not affect sickness responses. Only mice that lacked IL-1ß signaling in all endothelium including fenestrated capillaries lacked sickness responses. CONCLUSIONS: These experiments show that IL-1ß-induced sickness responses depend on intact IL-1ß signaling in blood vessels and suggest that fenestrated capillaries act as a critical signaling relay between the immune and nervous systems. TRIAL REGISTRATION: Not applicable.

Amplification and propagation of interleukin-1ß signaling by murine brain endothelial and glial cells.

BACKGROUND: During acute infections and chronic illnesses, the pro-inflammatory cytokine interleukin-1ß (IL-1ß) acts within the brain to elicit metabolic derangements and sickness behaviors. It is unknown which cells in the brain are the proximal targets for IL-1ß with respect to the generation of these illness responses. We performed a series of in vitro experiments to (1) investigate which brain cell populations exhibit inflammatory responses to IL-1ß and (2) examine the interactions between different IL-1ß-responsive cell types in various co-culture combinations. METHODS: We treated primary cultures of murine brain microvessel endothelial cells (BMEC), astrocytes, and microglia with PBS or IL-1ß, and then performed qPCR to measure inflammatory gene expression or immunocytochemistry to evaluate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. To evaluate whether astrocytes and/or BMEC propagate inflammatory signals to microglia, we exposed microglia to astrocyte-conditioned media and co-cultured endothelial cells and glia in transwells. Treatment groups were compared by Student's t tests or by ANOVA followed by Bonferroni-corrected t tests. RESULTS: IL-1ß increased inflammatory gene expression and NF-κB activation in primary murine-mixed glia, enriched astrocyte, and BMEC cultures. Although IL-1ß elicited minimal changes in inflammatory gene expression and did not induce the nuclear translocation of NF-κB in isolated microglia, these cells were more robustly activated by IL-1ß when co-cultured with astrocytes and/or BMEC. We observed a polarized endothelial response to IL-1ß, because the application of IL-1ß to the abluminal endothelial surface produced a more complex microglial inflammatory response than that which occurred following luminal IL-1ß exposure. CONCLUSIONS: Inflammatory signals are detected, amplified, and propagated through the CNS via a sequential and reverberating signaling cascade involving communication between brain endothelial cells and glia. We propose that the brain's innate immune response differs depending upon which side of the blood-brain barrier the inflammatory stimulus arises, thus allowing the brain to respond differently to central vs. peripheral inflammatory insults.

A longevity study with enhancer substances (selegiline, BPAP) detected an unknown tumor-manifestation-suppressing regulation in rat brain.

AIMS: First proof to show that (-)-deprenyl/selegiline (DEP), the first selective inhibitor of MAO-B, later identified as the first ß-phenylethylamine (PEA)-derived synthetic catecholaminergic activity enhancer (CAE) substance and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP), the tryptamine-derived presently known most potent, selective, synthetic enhancer substance, are specific markers of unknown enhancer-sensitive brain regulations. MAIN METHODS: Longevity study disclosing the operation of tumor-manifestation-suppressing (TMS) regulation in rat brain. Immonohistochemical identification of a fibromyxosarcoma in rats. Experiments with human medulloblastoma cell lines. Analysis of the mechanism of action of enhancer substances. KEY FINDINGS: Whereas 20/40 saline-treated rats manifested a fibromyxosarcoma, in groups of rats treated with 0.001mg/kg DEP: 15/40 rats; with 0.1mg/kg DEP: 11/40 rats (P<0.01); with 0.0001mg/kg BPAP: 8/40 rats (P<0.001); with 0.05mg/kg BPAP: 7/40 rats (P<0.01) manifested the tumor. Experiments with human medulloblastoma cell lines, HTB-186 (Daoy); UW-228-2, showed that BPAP was devoid of direct cytotoxic effect on tumor cells, and did not alter the direct cytotoxic effectiveness of temozolomide, cisplatin, etoposide, or vincristine. Interaction with distinct sites on vesicular monoamine-transporter-2 (VMAT2) is the main mechanism of action of the enhancer substances which clarifies the highly characteristic bi-modal, bell-shaped concentration-effect curves of DEP and BPAP. SIGNIFICANCE: Considering of the safeness of the enhancer substances and the finding that DEP and BPAP, specific markers of unknown enhancer sensitive brain regulations, detected the operation of an enhancer-sensitive TMS-regulation in rat brain, it seems reasonable to test in humans low dose DEP or BPAP treatment against the spreading of a malignant tumor.

The support needs of parents having a child with a chronic kidney disease: a focus group study.

BACKGROUND: Parents of children with a chronic kidney disease (CKD) have a crucial role in the management of their child's disease. The burden on parents is high: they are often exhausted, depressed and experience high levels of stress and a low quality of life, which could have a negative impact on their child's health outcomes. Support aiming at preventing and reducing parental stress is essential. Therefore, it is necessary to have insight in the problems and support needs among these parents. OBJECTIVE: Our aim is to describe parents' support needs regarding the problems they experience in having a child with CKD. METHODS: Five focus group interviews were conducted with parents of children: (i) with hereditary kidney disease, (ii) with nephrotic syndrome, (iii) with chronic kidney failure, (iv) using dialysis and (v) after renal transplantation. The children were treated at a paediatric nephrology unit in one university hospital in the Netherlands. The data were thematically analysed. RESULTS: Twenty-one parents participated in the focus groups. Parents need more information about their child's CKD and treatment options, and managing their own hobbies and work. Furthermore, parents need emotional support from their partner, family, friends, peers and healthcare professionals to help them cope with the disease of their child. Additionally, parents need practical support to hand over their care and support in transport, financial management and regarding their child at school. CONCLUSION: Needs regarding balancing their personal life are seldom prioritized by parents as the child's needs are considered more important. Therefore, it is important that healthcare professionals should not only attend to the abilities of parents concerning their child's disease management, but also focus on the parents' abilities in balancing their responsibilities as a caregiver with their own personal life.

Longevity study with low doses of selegiline/(-)-deprenyl and (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP).

AIMS: The first longevity study demonstrating that rats treated with the MAO-B inhibitory dose of (-)-deprenyl (0.25mg/kg) lived significantly longer than their saline-treated peers was published in 1988, and corroborated in many papers. The recent findings that (-)-deprenyl is primarily a PEA-derived synthetic catecholaminergic activity enhancer substance; (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine (BPAP) is a tryptamine-derived synthetic enhancer substance, initiated our first longevity study on rats with low enhancer doses of (-)-deprenyl and BPAP to test the enhancer effect's role in life extension. MAIN METHODS: We used the shuttle box technique for selecting the optimum doses of (-)-deprenyl and BPAP. (-)-Deprenyl exerts in rats in 0.001mg/kg its 'specific' enhancer effect and in 0.1mg/kg its 'non-specific' enhancer effect. BPAP exerts its 'specific' enhancer effect in 0.0001mg/kg and its 'non-specific' enhancer effect in 0.05mg/kg. Groups of male Wistar rats (N=40) were treated subcutaneously from their 10th week until death, three times weekly, with saline (0.5ml/kg), and the selected doses of (-)-deprenyl or BPAP, respectively. As an indicator of aging we tested the age-related changes in their learning ability. KEY FINDINGS: Rats treated with 0.0001 or 0.05mg/kg BPAP lived significantly longer than their saline treated peers (P<0.02) and BPAP was more potent in extending rats' lifespan than (-)-deprenyl. 18-month-old rats treated with 0.0001mg/kg BPAP were as good learners as 3-month-old saline treated rats. SIGNIFICANCE: The study revealed that the enhancer effect is responsible for life extension.

Excited state investigation of a new Ru(II) complex for dual reactivity with low energy light.

The new complex [Ru(tpy)(Me2dppn)(py)](2+) efficiently photodissociates py in CH3CN with Φ500 = 0.053(1) induced by steric bulk from methyl substituents and produces (1)O2 with ΦΔ = 0.69(9) from its long-lived (3)ππ* excited state. The unique excited state processes that result in dual reactivity were investigated using ultrafast transient absorption spectroscopy.

Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle.

Cachexia is a wasting condition defined by skeletal muscle atrophy in the setting of systemic inflammation. To explore the site at which inflammatory mediators act to produce atrophy in vivo, we utilized mice with a conditional deletion of the inflammatory adaptor protein myeloid differentiation factor 88 (MyD88). Although whole-body MyD88-knockout (wbMyD88KO) mice resist skeletal muscle atrophy in response to LPS, muscle-specific deletion of MyD88 is not protective. Furthermore, selective reexpression of MyD88 in the muscle of wbMyD88KO mice via electroporation fails to restore atrophy gene induction by LPS. To evaluate the role of glucocorticoids as the inflammation-induced mediator of atrophy in vivo, we generated mice with targeted deletion of the glucocorticoid receptor in muscle (mGRKO mice). Muscle-specific deletion of the glucocorticoid receptor affords a 71% protection against LPS-induced atrophy compared to control animals. Furthermore, mGRKO mice exhibit 77% less skeletal muscle atrophy than control animals in response to tumor growth. These data demonstrate that glucocorticoids are a major determinant of inflammation-induced atrophy in vivo and play a critical role in the pathogenesis of endotoxemic and cancer cachexia.

Relating centromeric topography in fixed human chromosomes to α-satellite DNA and CENP-B distribution.

Despite extensive analyses on the centromere and its associated proteins, detailed studies of centromeric DNA structure have provided limited information about its topography in condensed chromatin. We have developed a method with correlative fluorescence light microscopy and atomic force microscopy that investigates the physical and structural organization of α-satellite DNA sequences in the context of its associated protein, CENP-B, on human metaphase chromosome topography. Comparison of centromeric DNA and protein distribution patterns in fixed homologous chromosomes indicates that CENP-B and α-satellite DNA are distributed distinctly from one another and relative to observed centromeric ridge topography. Our approach facilitates correlated studies of multiple chromatin components comprising higher-order structures of human metaphase chromosomes.

Epigenetic control of female puberty.

The timing of puberty is controlled by many genes. The elements coordinating this process have not, however, been identified. Here we show that an epigenetic mechanism of transcriptional repression times the initiation of female puberty in rats. We identify silencers of the Polycomb group (PcG) as principal contributors to this mechanism and show that PcG proteins repress Kiss1, a puberty-activating gene. Hypothalamic expression of two key PcG genes, Eed and Cbx7, decreased and methylation of their promoters increased before puberty. Inhibiting DNA methylation blocked both events and resulted in pubertal failure. The pubertal increase in Kiss1 expression was accompanied by EED loss from the Kiss1 promoter and enrichment of histone H3 modifications associated with gene activation. Preventing the eviction of EED from the Kiss1 promoter disrupted pulsatile gonadotropin-releasing hormone release, delayed puberty and compromised fecundity. Our results identify epigenetic silencing as a mechanism underlying the neuroendocrine control of female puberty.

Multifunctional nanoparticles for dual imaging.

For imaging with different modalities, labels, which provide contrast for all modalities, are required. Colloidal nanoparticles composed out of an inorganic core and a polymer shell offer progress in this direction. Both, the core and the polymer shell, can be synthesized to be fluorescent, magnetic, or radioactive. When different cores are combined with different polymer shells, different types of particles for dual imaging can be obtained, as for example, fluorescent cores with radioactive polymer shells. Properties and perspectives of such nanoparticles for multimodal imaging are discussed.

Brain sex differences and hormone influences: a moving experience?

Sex differences in the nervous system come in many forms. Although a majority of sexually dimorphic characteristics in the brain have been described in older animals, mechanisms that determine sexually differentiated brain characteristics often operate during critical perinatal periods. Both genetic and hormonal factors likely contribute to physiological mechanisms in development to generate the ontogeny of sexual dimorphisms in brain. Relevant mechanisms may include neurogenesis, cell migration, cell differentiation, cell death, axon guidance and synaptogenesis. On a molecular level, there are several ways to categorize factors that drive brain development. These range from the actions of transcription factors in cell nuclei that regulate the expression of genes that control cell development and differentiation, to effector molecules that directly contribute to signalling from one cell to another. In addition, several peptides or proteins in these and other categories might be referred to as 'biomarkers' of sexual differentiation with undetermined functions in development or adulthood. Although a majority of sex differences are revealed as a direct consequence of hormone actions, some may only be revealed after genetic or environmental disruption. Sex differences in cell positions in the developing hypothalamus, and steroid hormone influences on cell movements in vitro, suggest that cell migration may be one target for early molecular actions that impact brain development and sexual differentiation.

Neuroendocrine plasticity in the anterior pituitary: gonadotropin-releasing hormone-mediated movement in vitro and in vivo.

The secretion of LH is cued by the hypothalamic neuropeptide, GnRH. After delivery to the anterior pituitary gland via the hypothalamic-pituitary portal vasculature, GnRH binds to specific high-affinity receptors on the surface of gonadotrope cells and stimulates synthesis and secretion of the gonadotropins, FSH, and LH. In the current study, GnRH caused acute and dramatic changes in cellular morphology in the gonadotrope-derived alphaT3-1 cell line, which appeared to be mediated by engagement of the actin cytoskeleton; disruption of actin with jasplakinolide abrogated cell movement and GnRH-induced activation of ERK. In live murine pituitary slices infected with an adenovirus-containing Rous sarcoma virus-green fluorescent protein, selected cells responded to GnRH by altering their cellular movements characterized by both formation and extension of cell processes and, surprisingly, spatial repositioning. Consistent with the latter observation, GnRH stimulation increased the migration of dissociated pituitary cells in transwell chambers. Our data using live pituitary slices are a striking example of neuropeptide-evoked movements of cells outside the central nervous system and in a mature peripheral endocrine organ. These findings call for a fundamental change in the current dogma of simple passive diffusion of LH from gonadotropes to capillaries in the pituitary gland.

The organisation of paediatric renal care in different European countries: results of the PAC project.

The Paediatric Access Care (PAC) project, organised by the Research Board of EDTNA/ERCA, aimed to study the organisation of paediatric renal care in Europe and to investigate the practice of access care for both haemodialysis (HD) and peritoneal dialysis (PD) paediatric patients. This paper reports on the organisation of paediatric renal care. The majority of paediatric renal care units were located in specific paediatric units of university hospitals. Most of the centres had offered HD, PD and transplantation (Tx) for more than 20 years. Half of nursing staff had qualifications in paediatric and renal nursing. Most of the centres offered an extended multidisciplinary team approach with the family actively involved in the care of the patient. PD and HD were equally used. Automatic Peritoneal Dialysis (APD) was offered as the standard PD treatment in 2 out of 3 centres. The HD schedule mostly utilised was 3 x 4 hours a week. Half of the patients were on the Tx waiting list and one third of registered patients were transplanted in 2004.

Paediatric access care in Europe: results of the Paediatric Access Care (PAC) project.

Part two of the Paediatric Access Care (PAC) project, a research project of EDTNA/ERCA, investigated PAC in HD and PD patients including the policy for the creation and maintenance of access, and the registration of access related complications that occurred during the registration year of 2004. Data were collected from 39 centres of 13 European countries and included 379 paediatric patients. Fatal complications, resulting in terminating the use of the access, were noted in 59 HD and 22 PD patients. Paediatric access care varied considerably between European centres and in many areas consensus or best practice evidence is still lacking. There is a need for recommendations for the paediatric renal nurse, handling access care in the paediatric renal population.

Live view of gonadotropin-releasing hormone containing neuron migration.

Neurons that synthesize GnRH control the reproductive axis and migrate over long distances and through different environments during development. Prior studies provided strong clues for the types of molecules encountered and movements expected along the migratory route. However, our studies provide the first real-time views of the behavior of GnRH neurons in the context of an in vitro preparation that maintains conditions comparable to those in vivo. The live views provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more changes in direction after they enter the brain. Perturbations of guiding fibers distal to moving GnRH neurons in the nasal compartment influenced movement without detectable changes in the fibers in the immediate vicinity of moving GnRH neurons. This suggests that the use of fibers by GnRH neurons for guidance may entail selective signaling in addition to mechanical guidance. These studies establish a model to evaluate the influences of specific molecules that are important for their migration.

Identification of four highly conserved genes between breakpoint hotspots BP1 and BP2 of the Prader-Willi/Angelman syndromes deletion region that have undergone evolutionary transposition mediated by flanking duplicons.

Prader-Willi and Angelman syndromes (PWS and AS) typically result from an approximately 4-Mb deletion of human chromosome 15q11-q13, with clustered breakpoints (BP) at either of two proximal sites (BP1 and BP2) and one distal site (BP3). HERC2 and other duplicons map to these BP regions, with the 2-Mb PWS/AS imprinted domain just distal of BP2. Previously, the presence of genes and their imprinted status have not been examined between BP1 and BP2. Here, we identify two known (CYFIP1 and GCP5) and two novel (NIPA1 and NIPA2) genes in this region in human and their orthologs in mouse chromosome 7C. These genes are expressed from a broad range of tissues and are nonimprinted, as they are expressed in cells derived from normal individuals, patients with PWS or AS, and the corresponding mouse models. However, replication-timing studies in the mouse reveal that they are located in a genomic domain showing asynchronous replication, a feature typically ascribed to monoallelically expressed loci. The novel genes NIPA1 and NIPA2 each encode putative polypeptides with nine transmembrane domains, suggesting function as receptors or as transporters. Phylogenetic analyses show that NIPA1 and NIPA2 are highly conserved in vertebrate species, with ancestral members in invertebrates and plants. Intriguingly, evolutionary studies show conservation of the four-gene cassette between BP1 and BP2 in human, including NIPA1/2, CYFIP1, and GCP5, and proximity to the Herc2 gene in both mouse and Fugu. These observations support a model in which duplications of the HERC2 gene at BP3 in primates first flanked the four-gene cassette, with subsequent transposition of these four unique genes by a HERC2 duplicon-mediated process to form the BP1-BP2 region. Duplicons therefore appear to mediate genomic fluidity in both disease and evolutionary processes.

A pharmacological analysis elucidating why, in contrast to (-)-deprenyl (selegiline), alpha-tocopherol was ineffective in the DATATOP study.

The Parkinson Study Group who conducted the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial designed their study in the belief that the MAO inhibitor (-)-deprenyl (selegiline), the antioxidant alpha-tocopherol, and the combination of the two compounds will slow the clinical progression of the disease to the extent that MAO activity and the formation of oxygen radicals contribute to the pathogenesis of nigral degeneration. In fact, (-)-deprenyl only delayed the onset of disability associated with early, otherwise untreated Parkinson's disease, however, in contrast to the expectation of the authors, alpha-tocopherol proved to be ineffective in the DATATOP study. Enhancer substances, (-)-deprenyl, (-)-1-phenyl-2-propylaminopentane [(-)-PPAP] the (-)-deprenyl analogue free of MAO inhibitory potency, and R-(-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP] the presently known most potent enhancer substance, are peculiar stimulants. They enhance the impulse propagation mediated release of the catecholamines in the brain. Due to their enhancer effect, the amount of catecholamines released from selected discrete brain areas (striatum, substantia nigra, tuberculum olfactorium, locus coeruleus) is significantly higher in rats treated with an enhancer substance than in saline treated rats. We compared the effect of (-)-deprenyl 0.025 and 0.25 mg/kg, (-)-PPAP 0.1 mg/kg, (-)-BPAP 0.0001 mg/kg, and alpha-tocopherol 25 and 50 mg/kg, in this test. The doses of (-)-deprenyl and alpha-tocopherol were selected to be in compliance with the dose given in the DATATOP study. Compared to saline treated rats, the enhancer substances significantly increased the amount of dopamine released from the striatum, substantia nigra and tuberculum olfactorium and the amount of norepinephrine released from the locus coeruleus; alpha-tocopherol was ineffective. The results indicate that alpha-tocopherol was ineffective, because, unlike (-)-deprenyl it dose not enhance the activity of the nigrostriatal dopaminergic neurons.

Analysis of the effect of (-)-BPAP, a selective enhancer of the impulse propagation mediated release of catecholamines and serotonin in the brain.

Endogenous and synthetic enhancer substances enhance in low concentration the impulse propagation mediated release of transmitters from the catecholaminergic and serotonergic neurons in the brain. The purpose of this study was to see whether uptake or MAO inhibition or agonists have similar enhancing prospectives as the enhancer substances. We measured the electrical stimulation induced release of [3H]-norepinephrine or [3H]-dopamine or [3H]-serotonin from the isolated brain stem of rats. (-)-1-Benzofuran-2-yl)-2-propylaminopentane HCl [(-)-BPAP] was used as a prototype of the enhancer compounds. 50 ng/ml (-)-BPAP was the most effective concentration in enhancing the nerve stimulation induced release of [3H]-norepinephrine and [3H]-dopamine, 10 ng/ml (-)-BPAP was highly effective in enhancing the release of [3H]-serotonin. In contrast, 250 ng/ml desmethylimipramine (DMI), a selective inhibitor of the uptake of norepinephrine, did not change significantly the nerve stimulation induced release of [3H]-norepinephrine and 50 ng/ml fluoxetine, a selective inhibitor of the uptake of serotonin, did not change the release of [3H]-serotonin. Neither 250 ng/ml clorgyline, a selective inhibitor of MAO-A, nor 250 ng/ml lazabemide, a selective inhibitor MAO-B, was capable to significantly increase the nerve stimulation induced release of either [3H]-serotonin or [3H]-norepinephrine. The potent dopamine receptor agonists, pergolide and bromocriptine did not change significantly the release of [3H]-dopamine in 50 ng/ml concentration, which is sufficient to stimulate the dopamine receptors. The results prove that stimulation of catecholaminergic and serotonergic neurons in the brain via the enhancing mechanism is clearly different from influencing uptake or MAO.

An HPLC tracing of the enhancer regulation in selected discrete brain areas of food-deprived rats.

The recent discovery of the enhancer regulation in the mammalian brain brought a different perspective to the brain-organized realization of goal-oriented behavior, which is the quintessence of plastic behavioral descriptions such as drive or motivation. According to this new approach, 'drive' means that special endogenous enhancer substances enhance the impulse-propagation-mediated release of transmitters in a proper population of enhancer-sensitive neurons, and keep these neurons in the state of enhanced excitability until the goal is reached. However, to reach any goal needs the participation of the catecholaminergic machinery, the engine of the brain. We developed a method to detect the specific enhancer effect of synthetic enhancer substances [(-)-deprenyl, (-)-PPAP, (-)-BPAP] by measuring the release of transmitters from freshly isolated selected discrete brain areas (striatum, substantia nigra, tuberculum olfactorium, locus coeruleus, raphe) by the aid of HPLC with electrochemical detection. To test the validity of the working hypothesis that in any form of goal-seeking behavior the catecholaminergic and serotonergic neurons work on a higher activity level, we compared the amount of norepinephrine, dopamine, and serotonin released from selected discrete brain areas isolated from the brain of sated and food-deprived rats. Rats were deprived of food for 48 and 72 hours, respectively, and the state of excitability of their catecholaminergic and serotonergic neurons in comparison to that of sated rats was measured. We tested the orienting-searching reflex activity of the rats in a special open field, isolated thereafter selected discrete brain areas and measured the release of norepinephrine, dopamine, and serotonin from the proper tissue samples into the organ bath. The orienting-searching reflex activity of the rats increased proportionally to the time elapsed from the last feed and the amount of dopamine released from the striatum, substantia nigra and tuberculum olfactorium, that of norepinephrine released from the locus coeruleus and that of serotonin released from the raphe increased significantly in the hungry rats proportionally to the time of fasting. For example: the amount of dopamine released from the substantia nigra of sated rats (4.62 +/- 0.20 nmoles/g wet weight) increased to 5.95 +/- 0.37 (P < 0.05) and 10.67 +/- 0.44 (P < 0.01) in rats deprived of food for 48 and 72 hours, respectively.

Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain.

Hundreds of millions of people now die over the age of 80 years primarily due to twentieth century progress in hygiene, chemotherapy, and immunology. With a longer average lifespan, the need to improve quality of life during the latter decades is more compelling. "Aging--The Epidemic of the New Millenium," a recent international conference (Monte Carlo, June 17-18, 2000), showed with peculiar clarity that a safe and efficient drug strategy to slow the age-related decay of brain performance is still missing. This review summarizes the physiologic and pharmacologic arguments in favor of a peculiar lifelong prophylactic medication with reasonable chances to keep in check brain aging and decrease the precipitation of age-related neurological diseases.