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PubMedDate not supplied

[Glutathione in cognitive function and neurodegeneration].

OBJECTIVE: To review the main findings on the glutathione role in cognitive function and synaptic plasticity processes, as well as, its involvement in neurotrophic and neurodegenerative events in rodents. DEVELOPMENT: The tripeptide glutathione and its related enzymes participate in the maintenance of oxidant homeostasis in aerobic cells. Oxidative damage to neuronal components underlies the molecular basis of neurodegeneration and brain aging. Several biomolecules with redox dependent activity are involved in the neuronal plasticity events that have a role in learning and memory functions. The maintenance of normal glutathione level is important for acquisition, but not consolidation, of spatial memory. Glutathione unavailability induces failures in hippocampal synaptic plasticity mechanisms, which are possibly related to a spatial memory deficit. On the other hand, several studies have suggested that the beneficial effects of neurotrophic treatments are mediated by the modulation of antioxidant defense mechanisms. In fact, nerve growth factor treatment to cognitively impaired rats stimulates glutathione reductase and can prevent the increases in glutathione peroxidase activity, pointing these enzymes as possible intracellular targets of neurotrophin actions on oxidant homeostasis. CONCLUSION: There is a closed link between glutathione metabolism and oxidant homeostasis, which is expressed in learning and synaptic plasticity deficits in conditions of low glutathione content, as well as, in neurodegeneration induced glutathione metabolism changes that can be prevented by neurotrophic treatment

Aging↗
PubMed1992

Effect of androgen on the expression of gap junction and beta-actin mRNAs in adult rat motoneurons.

Expression of gap junction and beta-actin mRNAs was examined in androgen-sensitive motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in adult male rats by in situ hybridization histochemistry using complementary DNAs encoding rat liver gap junction protein (connexin 32) and chick beta-actin. Hybridizable gap junction and beta-actin mRNAs were localised on the somata and proximal dendrites of SNB motoneurons. Removal of androgen by castration significantly reduced the expression levels of both gap junction and beta-actin mRNAs in the SNB motoneurons, whereas these changes were prevented by testosterone treatment. On the contrary, castration or testosterone treatment did not induce any changes in the expression levels of gap junction and beta-actin mRNAs in the motoneurons of the retrodorsolateral nucleus (RDLN), which accumulate androgen less frequently and sparsely than those in the SNB. These results suggest that androgen regulates the expression of both gap junction and beta-actin genes in the SNB motoneurons and may provide evidence for the molecular mechanisms of hormonally induced neuronal plasticity in the SNB motoneurons.

Actins↗
PubMed1997

Neurotrophin-3 signals redistribute RNA in neurons.

The translocation of specific mRNAs to dendrites and their potential for locally regulated translation are likely to serve as an effector in neuronal plasticity. Whether translation in dendrites is regulated by delivery of the RNA to sites of plasticity or a stationary pool of localized RNA undergoes enhanced translational efficiency is not clear. We show that RNA can translocate into dendrites in response to NT-3. RNA granules were visualized in cultured rat cortical neurons using the dye SYTO 14, which labels poly-ribosome complexes. Long before the morphological effects of NT-3 appeared, there was increased distal translocation of labeled complexes. This effect was blocked by K252a, a potent inhibitor of tyrosine kinase receptors. Therefore, neurons can utilize extracellular signals to alter the distribution of protein synthetic machinery via the active transport of RNA granules.

Animals↗
PubMed1993

Androgenic regulation of expression of beta-tubulin messenger ribonucleic acid in motoneurons of the spinal nucleus of the bulbocavernosus.

Expression of beta-tubulin mRNA was examined in androgen-sensitive motoneurons of the spinal nucleus of the bulbocavernosus (SNB) in adult male rats by in situ hybridization histochemistry using cDNA encoding mouse beta-tubulin. Hybridizable beta-tubulin mRNA was localized in the somata and proximal dendrites of SNB motoneurons. Removal of androgen by castration significantly reduced the expression level of beta-tubulin mRNA in the SNB motoneurons, whereas the change was prevented by testosterone treatment. On the contrary, castration or testosterone treatment did not induce any changes in the expression level of beta-tubulin mRNA in the androgen-insensitive motoneurons of the retrodorsolateral nucleus. These results suggest that androgen regulates the expression of beta-tubulin gene in the SNB motoneurons and may provide evidence for the molecular mechanisms of hormonally-induced neuronal plasticity in the SNB motoneurons.

Androgens↗
PubMed1992

Characterization of neuronal protein phosphatases in Aplysia californica.

Biochemical properties of neuronal protein phosphatases from Aplysia californica were characterized. Dephosphorylation of phosphorylase alpha by extracts of abdominal ganglia and clusters of sensory neurons from pleural ganglia was demonstrated. Type-1 protein phosphatase (PrP-1) was identified in these extracts by the dephosphorylation of the beta-subunit of phosphorylase kinase and its inhibition by the protein, inhibitor-2. Type-2A protein phosphatase (PrP-2A) was demonstrated by the dephosphorylation of the alpha-subunit of phosphorylase kinase, which was insensitive to inhibitor-2. As in vertebrate tissues, only four enzymes, PrP-1 (47%), PrP-2A (42%), PrP-2B (11%), and PrP-2C (less than 1%), accounted for all the cellular protein phosphatase activity dephosphorylating phosphorylase kinase. Aplysia PrP-1 and PrP-2A were potently inhibited by okadaic acid, with PrP-1 being approximately 20-fold more sensitive than PrP-2A. By comparison, purified PrP-2A from rabbit skeletal muscle was 15- to 20-fold more sensitive to okadaic acid than PrP-1 from the same source. Only PrP-1 was associated with the particulate fractions from Aplysia neurons, whereas PrP-1 and PrP-2A, -2B, and -2C were all present in the cytosol. Extraction of the particulate PrP-1 decreased its sensitivity to okadaic acid by sixfold, suggesting that cellular factor(s) affect its sensitivity to this inhibitor. In most respects, protein phosphatases from Aplysia neurons resemble their mammalian counterparts, and their biochemical characterization sets the stage for examining the role of these enzymes in neuronal plasticity, and in learning and memory.

Abdomen↗
PubMed2005

Role for calcium signaling and arachidonic acid metabolites in the activity-dependent increase of AHP amplitude in leech T sensory neurons.

Previous studies have revealed a new form of activity-dependent modulation of the afterhyperpolarization (AHP) in tactile (T) neurons of the leech Hirudo medicinalis. The firing of T cells is characterized by an AHP, which is mainly due to the activity of the Na+/K+ ATPase. Low-frequency repetitive stimulation of T neurons leads to a robust increment of the AHP amplitude, which is correlated with a synaptic depression between T neuron and follower cells. In the present study, we explored the molecular cascades underlying the AHP increase. We tested the hypothesis that this activity-dependent phenomenon was triggered by calcium influx during neural activity by applying blockers of voltage-dependent Ca2+ channels. We report that AHP increase requires calcium influx that, in turn, induces release of calcium from intracellular stores so sustaining the enhancement of AHP. An elevation of the intracellular calcium can activate the cytosolic isoforms of the phosholipase A2 (PLA2). Therefore we analyzed the role of PLA2 in the increase of the AHP, and we provide evidence that not only PLA2 but also the recruitment of arachidonic acid metabolites generated by the 5-lipoxygenase pathway are necessary for the induction of AHP increase. These data indicate that a sophisticated cascade of intracellular signals links the repetitive discharge of T neurons to the activation of molecular pathways, which finally may alter the activity of critical enzymes such as the Na+/K+ ATPase, that sustains the generation of the AHP and its increase during repetitive stimulation. These results also suggest the potential importance of the poorly studied 5-lipoxygenase pathway in forms of neuronal plasticity.

Animals↗
PubMed1998

Altered gravity modulates 5-lipoxygenase in human erythroleukemia K562 cells.

Mammalian lipoxygenases catalyse the first committed step in the so-called "arachidonate cascade", leading to the production of potent bioactive molecules, such as leukotrienes, lipoxins and hepoxilins. Leukotrienes interact with G protein-couple receptors involved in neuronal plasticity and T lymphocyte activation, lipoxins activate leukocytes, hepoxilines control the insulin release and stimulate the phospholipase C. Lipoxygenase (linoleate:oxygen oxidoreductase; E.C. 1.13.11.34; 5-LOX) are responsible for lymphocyte maturation and programmed death (apoptosis) of neuronal cells. Therefore, 5-LOX might be Space relevant, because among the most striking effects of Space enviroment are indeed those on T lymphocyte activation, neuronal cell growth and suspectedly apoptosis. In this study, the possible effects of the force of gravity on the activity and expression of 5-LOX have been investigated by subjecting human erythroleukemia K562 cells to simulated hypogravity or hypergravity.

Arachidonate 5-Lipoxygenase↗
PubMed2004

[Towards presymptomatic diagnosis, prevention and treatment of Alzheimer's disease].

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, the pathology of which becomes irreversible as it proceeds downstream of the disease cascade. Therefore, overcoming AD primarily requires early (presymptomatic) diagnosis, followed by preventive treatment. Since accumulation of amyloid beta peptide (A beta) in brain seems to play a central role AD pathogenesis, we established a new imaging technique to visualize A beta plaques in a mouse model of A beta amyloidosis in a non-invasive manner using a high-power MRI. This will open a new avenue to search for biochemical markers that correlate with the pathological parameters. We also found that a dimeric form of A beta, the quantity of which can be metabolically regulated by neprilysin, impairs in vivo neuronal plasticity, i.e. hippocampal long term potentiation. This suggests that reducing A beta dimers by upregulating neprilysin activity is likely to contribute to alleviation of memory-associated symptoms. Finally, we discovered that a neuropeptide, somatostatin, upregulates neuronal neprilysin activity. Because brain somatostatin expression is known to decline during aging, the finding indicates that the aging-induced downregulation of somatostatin may be a trigger for A beta accumulation leading to late-onset sporadic AD development and that somatostatin receptor(s) now emerge as pharmacological target candidates for the prevention and treatment of AD.

Alzheimer Disease↗
PubMed2001

Transient post-mating inhibition of behavioural and central nervous responses to sex pheromone in an insect.

Mating is costly for both male and female insects and should therefore only occur if it is likely to be successful. Within one scotophase, which is the dark period of the light cycle, male moths can only produce one single spermatophore, which is transferred to the female during mating. Remating within the same scotophase would thus be unsuccessful. We tested the hypothesis that newly mated males of the moth Agrotis ipsilon have developed an energy-saving strategy based on the transient inhibition of their sexual behaviour, thus avoiding unsuccessful remating. Agrotis ipsilon males do not copulate more than once during the same scotophase. Moreover, newly mated males do not respond behaviourally to the female sex pheromone although electroantennograms showed that their peripheral olfactory system is fully functional. However, intracellular recordings of antennal lobe neurons showed that the sensitivity for the synthetic sex pheromone blend decreased as compared with that of unmated males. Both the sexual behaviour and the sensitivity of the antennal lobe neurons were restored when tested during the next scotophase. Our results show a fast, transient neuronal plasticity that 'switches off' the olfactory system, which could prevent males from mating unsuccessfully.

Animals↗
PubMed1995

Inducible and constitutive transcription factor NF-kappa B-like DNA binding activities in rat brain cells cultured in vitro.

Description of constitutive and inducible transcription factors in brain cells is a prerequisite for understanding phenomena of long-term neuronal plasticity. In this report we report that basal levels of NF-kappa B-like transcription factor DNA binding activity (measured by electrophoretic mobility shift assay) are observed in two kinds of cultured rat brain cells, namely neurons of fetal cerebral hemispheres and astroglia derived from newborn brains. In the latter culture, phorbol ester induces additional forms of DNA binding activity, whereas L-glutamate fails to do so. In neurons, neither treatment is effective in inducing NF-kappa B-like DNA binding activity over the basal level. These results are in contrast to the fact that L-glutamate in both neurons and glia elevates DNA binding activity of AP-1, another transcription factor. These data, besides describing behavior of NF-kappa B-like DNA binding activities, also provide some evidence that L-glutamate exerts its modulatory functions on neurons and glia through specific transcription factors like AP-1.

Animals↗
PubMed1995

Stimulation of ionotropic glutamate receptors activates transcription factor NF-kappa B in primary neurons.

L-Glutamate is the most common excitatory neurotransmitter in the brain and plays a crucial role in neuronal plasticity as well as in neurotoxicity. While a large body of literature describes the induction of immediate-early genes, including c-fos, fosB, c-jun, junB, zif/268, and krox genes by glutamate and agonists in neurons, very little is known about preexisting transcription factors controlling the induction of such genes. This prompted us to investigate whether stimulation of glutamate receptors can activate NF-kappa B, which is present in neurons in either inducible or constitutive form. Here we report that brief treatments with kainate or high potassium strongly activated NF-kappa B in granule cells from rat cerebellum. This was detected at the single cell level by immunostaining with a monoclonal antibody that selectively reacts with the transcriptionally active, nuclear form of NF-kappa B p65. The activation of NF-kappa B could be blocked with the antioxidant pyrrolidine dithiocarbamate, suggesting the involvement of reactive oxygen intermediates. The data may explain the kainate-induced cell surface expression of major histocompatibility complex class I molecules, which are encoded by genes known to be controlled by NF-kappa B. Moreover, NF-kappa B activity was found to change dramatically in neurons during development of the cerebellum between days 5 and 7 after birth.

Animals↗
PubMed1992

Chronic cocaine treatment suppresses basal expression of zif268 in rat forebrain: in situ hybridization studies.

Transcription regulatory factors are rapidly induced in brain by a wide variety of stimuli and may be important in coordinating changes in gene expression underlying neuronal plasticity. In addition to the transient activation profile typically displayed by many of these genes, zif268 exhibits prominent basal expression in the brain that is dependent on synaptic activity. Accordingly, zif268 may play a key role in regulating neuronal gene expression induced by naturally occurring stimuli. Acute cocaine administration (15 mg/kg i.p.) produces a robust and transient induction of several transcription factors in the brain, including zif268. In the present study we report that, in contrast to the acute effects of a single dose, chronic cocaine treatment (15 mg/kg i.p., twice daily for a total of 10 injections), produces a widespread suppression of basal zif268 mRNA levels in rat forebrain between 8 and 24 hr after the last cocaine injection. This reduction is not evident after a single injection of cocaine or comparable chronic treatment with a structural analog, procaine, that does not share cocaine's uptake inhibitor properties. The suppression of basal zif268 expression may provide a mechanism for producing widespread effects of chronic cocaine administration on neuronal gene expression.

Animals↗
PubMed1997

GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine.

Parkinson's disease (PD) is characterized by the progressive loss of the substantia nigra (SN) dopaminergic neurons projecting to the striatum. Neurotrophic factors may have the potential to prevent or slow down the degenerative process occurring in PD. To that end, we examined whether low amounts of glial cell line-derived neurotrophic factor (GDNF) continuously released from polymer-encapsulated genetically engineered cells are able to prevent the loss of tyrosine hydroxylase immunoreactivity (TH-IR) in SN neurons and ameliorate the amphetamine-induced rotational asymmetry in rats that have been subjected to a unilateral medial forebrain bundle (MFB) axotomy. Baby hamster kidney (BHK) cells transfected with the cDNA for GDNF were encapsulated in a polymer fiber and implanted unilaterally at a location lateral to the MFB and rostral to the SN. ELISA assays before implantation show that the capsules release approximately 5 ng of GDNF/capsule per day. One week later, the MFB was axotomized unilaterally ipsilateral to the capsule placement. Seven days later, the animals were tested for amphetamine-induced rotational asymmetry and killed. The striatum was excised and analyzed either for catecholamine content or TH-IR, while the SN was immunostained for the presence of TH-IR. GDNF did not prevent the loss of dopamine in the striatum. However, GDNF significantly rescued TH-IR neurons in the SN pars compacta. Furthermore, GDNF also significantly reduced the number of turns per minute ipsilateral to the lesion under the influence of amphetamine. Improvement of rotational behavior in the absence of dopaminergic striatal reinnervation may reflect neuronal plasticity in the SN, as suggested by the dendritic sprouting observed in animals receiving GDNF. These results illustrate that the continuous release of low levels of GDNF close to the SN is capable of protecting the nigral dopaminergic neurons from an axotomy-induced lesion and significantly improving pharmacological rotational behavior by a mechanism other than dopaminergic striatal reinnervation.

Animals↗
PubMed1998

Dexamethasone induces hypertrophy of developing medial septum cholinergic neurons: potential role of nerve growth factor.

Glucocorticoid hormones influence neuronal plasticity during development; however little is known about the mechanisms of this trophic activity. Because glucocorticoids increase nerve growth factor (NGF) synthesis in selected brain areas and NGF plays a role in the development of basal forebrain cholinergic neurons, we tested the hypothesis that glucocorticoids may foster maturation of the cholinergic phenotype during postnatal development via the induction of NGF biosynthesis. The synthetic glucocorticoid dexamethasone (DEX) was injected systemically (0.5 mg/kg, s.c.) once a day for 1 week in 7-d-old (P7) rats. DEX elicited an increase in NGF mRNA and protein levels in the cerebral cortex and hippocampus as well as specific NGF responses, such as TrkA tyrosine phosphorylation in the septum, choline acetyltransferase (ChAT) and p75 neurotrophin receptor (p75NTR) immunoreactivity, and a relative number of cholinergic neurons in the medial septum. To examine whether the effect of DEX is age-related, we treated 1- and 14-d-old rats with DEX for 1 week. DEX increased NGF expression in rats treated from P1 to P8 but not in those treated from P14 to P21. The age-related increased expression of NGF correlated with the induction of ChAT immunoreactivity in the medial septum. Moreover, in the spinal cord, neither NGF nor ChAT levels were increased by DEX, suggesting that the glucocorticoid-mediated changes seen in the basal forebrain are associated with specific NGF responses. Our data suggest that by increasing NGF levels, glucocorticoids may play a role in the maturation of postnatal cholinergic neurons.

Age Factors↗
PubMed1994

Calcium/calmodulin-dependent protein kinase II immunostaining is preserved in Alzheimer's disease hippocampal neurons.

Alterations in protein phosphorylation may be important in the pathogenesis of Alzheimer's disease and recent observations suggest that a subset of protein kinase pathways may be selectively altered. Calcium/calmodulin-dependent protein kinase II CaM kinase II) is the most abundant protein kinase in the brain and is believed to play an important role in the regulation of synaptic transmission, long-term potentiation and other forms of neuronal plasticity. We have now evaluated brains of individuals with Alzheimer's disease for changes in the distribution and density of immunoreactivity for the alpha subunit of CaM kinase II. CaM kinase II immunoreactivity was found in cytoarchitectural areas and neurons vulnerable to the formation of neurofibrillary angles and senile plaques. Over 80% of neurons bearing neurofibrillary tangles expressed CaM kinase II. Loss of CaM kinase II immunoreactivity was found in CA1, commensurate with neuronal loss in this area. Remaining CA1 neurons, however, had preserved CaM kinase II immunoreactivity. Preservation in the distribution and density of CaM kinase II immunoreactivity was observed in other hippocampal regions and in a multimodal association area, area 20. These results suggest CaM kinase II expression in the Alzheimer's disease brain is unaltered despite marked neuropathological changes.

Aged↗
PubMed1998

Acute stress facilitates long-lasting changes in cholinergic gene expression.

Acute traumatic stress may lead to post-traumatic stress disorder (PTSD), which is characterized by delayed neuropsychiatric symptoms including depression, irritability, and impaired cognitive performance. Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetylcholinesterase may induce psychopathologies that are reminiscent of PTSD. It is unknown how a single stressful event mediates long-term neuronal plasticity. Moreover, no mechanism has been proposed to explain the convergent neuropsychological outcomes of stress and of acetylcholinesterase inhibition. However, acute stress elicits a transient increase in the amounts released of the neurotransmitter acetylcholine and a phase of enhanced neuronal excitability. Inhibitors of acetylcholinesterase also promote enhanced electrical brain activity, presumably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes that regulate acetylcholine availability after stress and blockade of acetylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of neuronal excitability. Both of these phases are mediated by muscarinic acetylcholine receptors. Our results suggest a model in which robust cholinergic stimulation triggers rapid induction of the gene encoding the transcription factor c-Fos. This protein then mediates selective regulatory effects on the long-lasting activities of genes involved in acetylcholine metabolism.

Acetylcholine↗
PubMedDate not supplied

[Senescence process of mnesic centers: a study in humans and rats].

The age-related neuronal changes in mnemonic centres were studied in 37 human and 36 rats (Wistar) brains. The age of the brains (without cerebral alterations) was uniformly distributed along the lifespan (16-86 years in humans and 1-36 months in rats). The results showed parallel changes in humans and rats. The neuronal loss oscillated between 3 and 64%, mean 32%. Neuronal death was a continuous process, although there were differences according the centres, for instance, the higher loss was found in the first half of life in the cortex entorhinalis and hippocampus (rat), and the contrary happened in the dorsolateral and basomedial nucleus of amygdala. In other centres, e.g., mamilla body, basal nucleus of Meynert etc. the loss was quite uniform. The modification in nuclear size showed 3 different phases: there was an initial period in which the nuclear area decreased, a second period with an increase and, in the last period, there was a stabilization in humans and a conspicuous decrease in rats. The nuclear enlargement is interpreted as result of the loss of redundance in nervous centres and the stabilization or atrophy as a consequence of loss of the neuronal plasticity.

Adolescent↗
PubMed1981

Schilder's disease. A study of the cerebral cortex with Golgi's method.

The cerebral cortex of a patient with Schilder's disease was studied with the Golgi method. The number of synaptic spines, basal dendrites, branching points, and dendritic intersection points of 5th layer pyramids are similar to those of controls, in spite of almost complete loss of extrinsic fibers. These data illustrate the probable remodeling of intrinsic cortical circuits and neuronal plasticity in the human cerebral cortex.

Cerebral Cortex↗