Biomedical subjects

R Quirion

Publications and source records attributed to R Quirion.

At least 37 records · Page 2Linked to original sources

PubMed2001

Nerve growth factor rapidly induces prolonged acetylcholine release from cultured basal forebrain neurons: differentiation between neuromodulatory and neurotrophic influences.

Long-term exposure to nerve growth factor (NGF) is well established to have neurotrophic effects on basal forebrain cholinergic neurons, but its potential actions as a fast-acting neuromodulator are not as well understood. We report that NGF (0.1-100 ng/ml) rapidly (<60 min) and robustly enhanced constitutive acetylcholine (ACh) release (148-384% of control) from basal forebrain cultures without immediate persistent increases in choline acetyltransferase activity. More ACh was released in response to NGF when exposure was coupled with a higher depolarization level, suggesting activity dependence. In a long-term potentiation-like manner, brief NGF exposure (10 ng/ml; 60 min) induced robust and prolonged increases in ACh release, a capacity that was shared with the other neurotrophins. K252a (10-100 nm), BAPTA-AM (25 microm), and Cd(2+) (200 microm) prevented NGF enhancement of ACh release, suggesting the involvement of TrkA receptors, Ca(2+), and voltage-gated Ca(2+) channels, respectively. Forskolin (10 microm), a cAMP generator, enhanced constitutive ACh release but did not interact synergistically with NGF. Tetrodotoxin (1 microm) and cycloheximide (2 microm) did not prevent NGF-induced ACh release, indicative of action at the level of the cholinergic nerve terminal and that new protein synthesis is not required for this neurotransmitter-like effect, respectively. In contrast, after a 24 hr NGF treatment, distinct protein synthesis-dependent and independent effects on choline acetyltransferase activity and ACh release were observed. These results indicate that neuromodulator/neurotransmitter-like (protein synthesis-independent) and neurotrophic (translation-dependent) actions likely make distinct contributions to the enhancement of cholinergic activity by NGF.

Acetylcholine↗

PubMed2001

Application of in vivo microdialysis to the study of cholinergic systems.

The application of in vivo microdialysis to the study of acetylcholine (ACh) release has contributed greatly to our understanding of cholinergic brain systems. This article reviews standard experimental procedures for dialysis probe selection and implantation, perfusion parameters, neurochemical detection, and data analysis as they relate to microdialysis assessments of cholinergic function. Particular attention is focused on the unique methodological considerations that arise when in vivo microdialysis is dedicated expressly to the recovery and measurement of ACh as opposed to other neurotransmitters. Limitations of the microdialysis technique are discussed, as well as methodological adaptations that may prove useful in overcoming these limitations. This is followed by an overview of recent studies in which the application of in vivo microdialysis has been used to characterize the basic pharmacology and physiology of cholinergic neurons. Finally, the usefulness of the microdialysis approach for testing hypotheses regarding the cholinergic systems' involvement in cognitive processes is examined. It can be concluded that, in addition to being a versatile and practical method for studying the neurochemistry of cholinergic brain systems, in vivo microdialysis represents a valuable tool in our efforts to better comprehend ACh's underlying role in a variety of behavioral processes.

Acetylcholine↗

PubMed2001

Say NO to Alzheimer's disease: the putative links between nitric oxide and dementia of the Alzheimer's type.

Alzheimer's disease (AD) is the most common form of dementia, with progressive cognitive deficits being the primary symptom. AD is neuropathologically characterized by amyloid and neurofibrillary tangle depositions, basal forebrain cholinergic deficit, and extensive neuronal loss and synaptic changes in the cortex and hippocampus. Mutations of amyloid precursor protein or presenilin genes or apolipoprotein E gene polymorphism appear to affect amyloid formation, which in turn causes neuronal death via a number of possible mechanisms, including Ca(2+) homeostasis disruption, oxidative stress, excitotoxicity, energy depletion, neuro-inflammation and apoptosis. Nitric oxide (NO) is an enzymatic product of nitric oxide synthase, which exists in three isoforms. In addition to its vasoactive and immunological properties, NO has significant neurophysiological functions. However, NO can also be neurotoxic primarily due to its free radical properties, and it has been implicated in neurodegenerative diseases. Interestingly, there is increasing evidence that NO may have a role in the aforementioned AD pathogenetic mechanisms, and putative links between NO and AD are beginning to be recognized. This review focuses on these issues highlighting the possible relevance of NO in AD, either as a neuroprotective or neurotoxic agent.

Alzheimer Disease↗

PubMed2001

DNA microarrays in neuropsychopharmacology.

Recent advances in experimental genomics, coupled with the wealth of sequence information available for a variety of organisms, have the potential to transform the way pharmacological research is performed. At present, high-density DNA microarrays allow researchers to quickly and accurately quantify gene-expression changes in a massively parallel manner. Although now well established in other biomedical fields, such as cancer and genetics research, DNA microarrays have only recently begun to make significant inroads into pharmacology. To date, the major focus in this field has been on the general application of DNA microarrays to toxicology and drug discovery and design. This review summarizes the major microarray findings of relevance to neuropsychopharmacology, as a prelude to the design and analysis of future basic and clinical microarray experiments. The ability of DNA microarrays to monitor gene expression simultaneously in a large-scale format is helping to usher in a post-genomic age, where simple constructs about the role of nature versus nurture are being replaced by a functional understanding of gene expression in living organisms.

Aging↗

PubMed2001

Agonist and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226.

Neuropeptide FF (NPFF) is a part of a neurotransmitter system acting as a modulator of endogenous opioid functions. At this time, no non-peptide or peptide NPFF-antagonists have been discovered. Here, we demonstrate that Neuropeptide Y (NPY) ligands, in fact possess significant ability to interact with the human NPFF(2) receptors. NPY Y(1) antagonist BIBP3226 and mixed Y(1) antagonist/Y(4) agonist GR231118 are able to displace with low affinity, 50 -- 100 nM, the specific binding on NPFF receptors expressed in CHO cells as well as in rat dorsal spinal cord, an affinity however superior to those determined against Y(2), Y(4) or Y(5) receptors. Furthermore, BIBP3226 which is unable to inhibit the forskolin-stimulated cyclic AMP production mediated by NPFF(2) receptors, antagonizes the effect of NPFF, revealing the first antagonist of NPFF receptors. These properties of NPY ligands on Neuropeptide FF receptors must be considered when evaluating pharmacological activities of these drugs.

Animals↗

PubMed2001

Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity.

Beta amyloid (Abeta) is implicated in Alzheimer's disease (AD). Abeta(1 - 42) (5, 10, or 20 microM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures. L-NOARG and SMTC (both at 10 or 100 microM) - type I NOS inhibitors - reduced cellular NO release in the absence of Abeta(1 - 42). At 100 microM, both drugs decreased cell viability. L-NIL (10 or 100 microM), and 1400W (1 or 5 microM) - type II NOS inhibitors - reduced NO release and improved viability when either drug was administered up to 4 h post Abeta(1 - 42) (10 microM) treatment. L-NOARG and SMTC (both at 10 or 100 microM) were only able to decrease NO release. Carboxy-PTIO or Trolox (both at 10 or 100 microM) - a NO scavenger and an antioxidant, respectively - increased viability when administered up to 1 h post Abeta(1 - 42) treatment. Either L-NIL (50 microM) or 1400W (3 microM) and Trolox (50 microM) showed synergistic actions. Peroxynitrite (100 or 200 microM) reduced cell viability. Viabilities were improved by L-NIL (100 microM), 1400W (5 microM), carboxy-PTIO (10 or 100 microM), and Trolox (10 or 100 microM). Hence, the data show that Abeta(1 - 42) induced NO release in neurons and glial cells, and that Abeta neurotoxicity is, at least in part, mediated by NO. NO concentration modulating compounds and antioxidant may have therapeutic importance in neurological disorders where oxidative stress is likely involved such as in AD.

Amyloid beta-Peptides↗

PubMed2001

Strain differences in the behavioural outcome of neonatal ventral hippocampal lesions are determined by the postnatal environment and not genetic factors.

It has been demonstrated that not only do rats neonatally lesioned in the ventral hippocampus (VH) develop behavioural hypersensitivity to amphetamine postpubertally, but also that the expression of the sensitivity is strain specific. For example, excitotoxic VH lesions at postnatal day (PD) 7 lead to significant increases in amphetamine-induced locomotion in postpubertal Fischer rats, but not in Lewis rats. However, as it is likely that the effect of strain differences are due to a combination of genetics and environment, we examined the contributions of the environment of the pups in determining the behavioural outcome following neonatal VH lesions. Fisher and Lewis rat pups were cross-fostered at birth, and then at PD7 lesioned bilaterally in the VH with ibotenic acid. ANOVA analysis of postpubertal amphetamine-induced locomotor data revealed a significant effect of the strain of the dams raising the pups but no effect of the strain of the pup. In addition, a post hoc analysis revealed that lesioned Fisher or Lewis rats raised by Fisher, but not those raised by Lewis, dams demonstrated amphetamine-induced hyperlocomotion relative to nonlesioned controls. Observations of the maternal behaviour of Fischer and Lewis dams revealed significant differences in the frequency of arched-back nursing between the two strains. Interestingly, a correlation of the frequency of arched back nursing vs novelty- or amphetamine-induced locomotion revealed that the lesioned rats were significantly more affected by increases in arched-back nursing compared to the controls. The results suggest that the genetic background of the pups does not significantly affect the behavioural outcome following neonatal VH lesions; however, the results do suggest an important role of early environmental variables on the behavioural outcome of neonatal VH lesions.

Amphetamine↗

PubMed2001

Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study.

Tolerance to opiates reduces their effectiveness in the treatment of severe pain. Although the mechanisms are unclear, overactivity of pro-nociceptive systems has been proposed to contribute to this phenomenon. We have reported that the development of morphine tolerance significantly increased calcitonin-gene-related-peptide-like immunoreactivity (CGRP-IR) in primary sensory afferents of the spinal dorsal horn, suggesting that changes in pain-related neuropeptides in the dorsal root ganglion (DRG) neurons may be involved (Menard et al., 1996, J. Neurosci., 16, 2342-2351). Recently, we have shown that repeated morphine treatments induced increases in CGRP- and substance P (SP)-IR in cultured DRG, mimicking the in vivo effects (Ma et al., 2000, Neuroscience, 99, 529-539). In this study, we investigated the intracellular signal transduction pathways possibly involved in morphine-induced increases in CGRP- and SP-IR in DRG neurons. Repeated morphine exposure (10-20 microm) for 6 days increased the number of neurons expressing phosphorylated (p) mitogen-activated protein (MAP) kinases, including the extracellular signal-regulated kinase (pERK), c-jun N-terminal kinase (pJNK) and P38 (pP38 MAPK). The number of neurons expressing phosphorylated cAMP responsive element binding protein (pCREB) was also markedly increased in morphine-exposed cultured DRG neurons. pERK-, pP38-, pJNK- and pCREB-IR were colocalized with CGRP-IR in cultured DRG neurons. Naloxone effectively blocked these actions of morphine, whereas a selective MEK1 inhibitor, PD98059, inhibited the morphine-induced increase in the phosphorylation of ERK and CREB, and the expression of CGRP and SP. Moreover, in morphine-tolerant rats, the number of pCREB-, CGRP- and SP-IR neurons in the lumbar DRG was also significantly increased. These in vitro and in vivo data suggest that the phosphorylation of MAP kinases and CREB plays a role in the morphine-induced increase in spinal CGRP and SP levels in primary sensory afferents, contributing to the development of tolerance to opioid-induced analgesia.

Animals↗

PubMed2001

Effects of amyloid peptides on cell viability and expression of neuropeptides in cultured rat dorsal root ganglion neurons: a role for free radicals and protein kinase C.

Chronic pain caused by nerve injury and inflammation is more common in the elderly. However, mechanisms underlying this phenomenon are unclear. Higher sensitivity of sensory neurons to free radicals has been suggested as one possibility. The production of free radicals can be induced by various agents, including the highly toxic protein beta-amyloid (A beta), which is found in higher amounts in the brains of Alzheimer's Disease patients. In dorsal root ganglion (DRG) cultures exposed to A beta, we examined cellular toxicity and peptide expression, in particular calcitonin gene-related peptide (CGRP), a peptide which is abundantly expressed by nociceptive afferents and is known to be involved in pain processes. Exposure of cultured rat DRG neurons to A beta(25--35) or A beta(1--40) (10 or 20 microM for 24--96 h) increased trypan blue-stained cells in a concentration- and time-dependent manner, thus, indicating cellular toxicity. These treatments also increased the number of CGRP immunoreactive (IR) neurons while decreasing the number of neuropeptide Y- and galanin-IR neurons. The free radical scavenger, superoxide dismutase, attenuated both the toxicity and neuropeptide changes induced by A beta, thus, suggesting that oxidative stress probably contributes to these effects. Exposure of cultured DRG neurons to A beta also increased the number of protein kinase C alpha (PKC alpha)-IR neurons. The PKC inhibitors, chelerythrine chloride and Gö6976, significantly augmented A beta-induced cellular toxicity while attenuating the increases in CGRP-and PKC alpha-IR cells, supporting the notion of a protective role for PKC in A beta insults. These in vitro data suggest that A beta peptides may, in addition to causing neurotoxicity, regulate neuropeptide expression in primary afferents. This finding could be relevant to the higher incidence of neuropathic pain that occurs with ageing.

Amyloid beta-Peptides↗

PubMed2001

The chemokine interleukin-8 acutely reduces Ca(2+) currents in identified cholinergic septal neurons expressing CXCR1 and CXCR2 receptor mRNAs.

The chemokine IL-8 is known to be synthesized by glial cells in the brain. It has traditionally been shown to have an important role in neuroinflammation but recent evidence indicates that it may also be involved in rapid signaling in neurons. We investigated how IL-8 participates in rapid neuronal signaling by using a combination of whole-cell recording and single-cell RT-PCR on dissociated rat septal neurons. We show that IL-8 can acutely reduce Ca(2+) currents in septal neurons, an effect that was concentration-dependent, involved the closure of L- and N-type Ca(2+) channels, and the activation of G(ialpha1) and/or G(ialpha2) subtype(s) of G-proteins. Analysis of the mRNAs from the recorded neurons revealed that the latter were all cholinergic in nature. Moreover, we found that all cholinergic neurons that responded to IL-8, expressed mRNAs for either one or both IL-8 receptors CXCR1 and CXCR2. This is the first report of a chemokine that modulates ion channels in neurons via G-proteins, and the first demonstration that mRNAs for CXCR1 are expressed in the brain. Our results suggest that IL-8 release by glial cells in vivo may activate CXCR1 and CXCR2 receptors on cholinergic septal neurons and acutely modulate their excitability by closing calcium channels.

Acetylcholine↗

PubMed2001

Neurotrophins differentially enhance acetylcholine release, acetylcholine content and choline acetyltransferase activity in basal forebrain neurons.

Several lines of evidence indicate that nerve growth factor is important for the development and maintenance of the basal forebrain cholinergic phenotype. In the present study, using rat primary embryonic basal forebrain cultures, we demonstrate the differential regulation of functional cholinergic markers by nerve growth factor treatment (24--96 h). Following a 96-h treatment, nerve growth factor (1--100 ng/mL) increased choline acetyltransferase activity (168--339% of control), acetylcholine content (141--185%), as well as constitutive (148--283%) and K(+)-stimulated (162--399%) acetylcholine release, but increased release was not accompanied by increased high-affinity choline uptake. Enhancement of ACh release was attenuated by vesamicol (1 microM), suggesting a vesicular source, and was abolished under choline-free conditions, emphasizing the importance of extracellular choline as the primary source for acetylcholine synthesized for release. A greater proportion of acetylcholine released from nerve growth factor-treated cultures than from nerve growth factor-naïve cultures was blocked by voltage-gated Ca(2+) channel antagonists, suggesting that nerve growth factor modified this parameter of neurotransmitter release. Cotreatment of NGF (20 ng/mL) with K252a (200 nM) abolished increases in ChAT activity and prevented enhancement of K(+)-stimulated ACh release beyond the level associated with K252a, suggesting the involvement of TrkA receptor signaling. Also, neurotrophin-3, neurotrophin-4 and brain-derived neurotrophic factor (all at 5--200 ng/mL) increased acetylcholine release, although they were not as potent as nerve growth factor and higher concentrations were required. High brain-derived neurotrophic factor concentrations (100 and 200 ng/mL) did, however, increase release to a level similar to nerve growth factor. In summary, long-term exposure (days) of basal forebrain cholinergic neurons to nerve growth factor, and in a less-potent fashion the other neurotrophins, enhanced the release of acetylcholine, which was dependent upon a vesicular pool and the availability of extracellular choline.

Acetylcholine↗

PubMed2000

Insulin-like growth factor-I and its receptor in the frontal cortex, hippocampus, and cerebellum of normal human and alzheimer disease brains.

Assimilated evidence indicates that the neurotoxic potential of amyloid beta (Abeta) peptide and an alteration in the level of growth factor(s) may possibly be involved in the loss of neurons observed in the brain of patients suffering from Alzheimer disease (AD), the prevalent cause of dementia in the elderly. In the present study, using receptor binding assays and immunocytochemistry, we evaluated the pharmacological profile of insulin-like growth factor-I (IGF-I) receptors and the distribution of IGF-I immunoreactivity in the frontal cortex, hippocampus, and cerebellum of AD and age-matched control brains. In control brains, [(125)I]IGF-I binding was inhibited more potently by IGF-I than by Des(1-3)IGF-I, IGF-II or insulin. The IC(50) values for IGF-I in the frontal cortex, hippocampus, and cerebellum of the normal brain did not differ significantly from the corresponding regions of the AD brain. Additionally, neither K(D) nor B(max) values were found to differ in the hippocampus of AD brains from the controls. At the regional levels, [(125)I]IGF-I binding sites in the AD brain also remained unaltered compared to the controls. As for the peptide itself, IGF-I immunoreactivity, in normal control brains, was evident primarily in a subpopulation of astrocytes in the frontal cortex and hippocampus, and in certain Purkinje cells of the cerebellum. In AD brains, a subset of Abeta-containing neuritic plaques, apart from astrocytes, exhibit IGF-I immunoreactivity. These results, taken together, suggest a role for IGF-I in compensatory plasticity and/or survival of the susceptible neurons in AD brains.

Aged↗

PubMed2000

Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC12 cells.

The Forkhead family transcription factor FKHRL1, a mammalian homolog of DAF16 in the nematode Caenorhabditis elegans, is an inducer of apoptosis in its unphosphorylated form and was recently reported as a substrate of Akt kinases. Insulin-like growth factor (IGF-1) is a potent stimulant of Akt kinase, leading to inhibition of the apoptotic pathway. In this study, we characterized the phosphorylation of FKHRL1 induced by IGF-1 in PC12 cells and various neuronal cell types and examined the potential role of Akt in this regard. IGF-1 rapidly induced the phosphorylation of Akt and FKHRL1 in PC12 cells. The phosphorylation of Akt and FKHRL1 induced by 10 nm IGF-1 was inhibited by the phosphatidylinositide 3-kinase (PI3K) inhibitors wortmannin (0.25-2 microm) and LY294002 (12.5-100 microm), but not by the MEK inhibitor PD98059 (50 microm) or the p70 S6 kinase pathway inhibitor rapamycin (50 nm), suggesting that the phosphorylation of FKHRL1 induced by IGF-1 is mediated by the PI3K pathway. As observed for IGF-1, an in vitro kinase assay with purified active Akt kinase demonstrated that the kinase is capable of directly phosphorylating FKHRL1 at Thr(32) and Ser(253), leading to inhibition of its pro-apoptotic properties. Moreover, transient expression of constitutively active Akt (MS-Akt, where MS is a myristylation signal) increased the phosphorylation of FKHRL1, whereas the expression of kinase-dead Akt (M179A Akt) attenuated the phosphorylation of FKHRL1 induced by 10 nm IGF-1 in PC12 cells. Interestingly, FKHRL1 co-immunoprecipitated with Akt in PC12 cells, indicating that these two proteins can associate in these cells. As IGF-1 also induced the phosphorylation of FKHRL1 in primary cortical and cerebellar neuronal cultures, these data, taken together, demonstrate that IGF-1, acting via the PI3K/Akt kinase pathway, can regulate the phosphorylation of FKHRL1, leading to inhibition of this apoptotic transcription factor in neuronal cells.

3T3 Cells↗

PubMed2000

Behavioral insensitivity to restraint stress, absent fear suppression of behavior and impaired spatial learning in transgenic rats with hippocampal neuropeptide Y overexpression.

Exogenous neuropeptide Y (NPY) reduces experimental anxiety in a wide range of animal models. The generation of an NPY-transgenic rat has provided a unique model to examine the role of endogenous NPY in control of stress and anxiety-related behaviors using paradigms previously used by pharmacological studies. Locomotor activity and baseline behavior on the elevated plus maze were normal in transgenic subjects. Two robust phenotypic traits were observed. (i) Transgenic subjects showed a markedly attenuated sensitivity to behavioral consequences of stress, in that they were insensitive to the normal anxiogenic-like effect of restraint stress on the elevated plus maze and displayed absent fear suppression of behavior in a punished drinking test. (ii) A selective impairment of spatial memory acquisition was found in the Morris water maze. Control experiments suggest these traits to be independent. These phenotypic traits were accompanied by an overexpression of prepro-NPY mRNA and NPY peptide and decreased NPY-Y1 binding within the hippocampus, a brain structure implicated both in memory processing and stress responses. Data obtained using this unique model support and extend a previously postulated anti-stress action of NPY and provide novel evidence for a role of NPY in learning and memory.

Animals↗

PubMed2000

Stimulation of protein kinase C modulates insulin-like growth factor-1-induced akt activation in PC12 cells.

Activation of protein kinase C (PKC) plays an important role in the negative regulation of receptor signaling, but its effect on insulin-like growth factor-1 (IGF-1) receptor signaling remains unclear. In this study, we characterized the intracellular pathways involved in IGF-1-induced activation of Akt and evaluated the effects of the PKC activator phorbol 12-myristate 13-acetate (PMA) on the Akt activation by IGF-1. IGF-1 induced a time- and concentration-dependent activation of Akt. The effect of IGF-1 was blocked by the phosphatidylinositide 3-kinase (PI3K) inhibitors LY294002 (50 micrometer) and wortmannin (0.5 micrometer), but not by the MEK inhibitor PD98059 (50 micrometer) or the p70 S6 kinase pathway inhibitor rapamycin (50 nm), suggesting that the stimulation of Akt by IGF-1 is mediated by the PI3K pathway. Interestingly, cotreatment with PMA (400 nm) attenuated IGF-1-induced activation of Akt. The attenuation was blocked completely by the PKC inhibitor GO6983 (0.5 micrometer), but only partially by the MEK inhibitor PD98059 (50 micrometer), indicating that MAPK-dependent and -independent pathways are involved. PMA induced the activation of PKC in PC12 cells, and this induction was blocked by GO6983. These data further support the role of PKC in the effect of PMA. Moreover, PKCdelta is likely involved in the action of PMA on the basis of data obtained using isoform-specific inhibitors such as rottlerin. PMA also decreased IGF-1-induced tyrosine phosphorylation of insulin receptor substrate-1 and its association with PI3K. Taken together, these results suggest, for the first time, that stimulation of PKC modulates IGF-1-induced activation of Akt.

Animals↗

PubMed2000

Dopamine D-5 receptor modulates hippocampal acetylcholine release.

Dopamine is intimately involved in cognitive processes in the brain. Of the several subtypes of dopamine receptors, the possible role of dopamine D1-like receptors in brain functions, especially in learning and memory, has recently generated much interest. However, molecularly the D1-like receptors are comprised of at least two subtypes, namely D-1 and D-5, and it has not been possible to ascertain which of these two receptor classes is responsible for these functions due to the lack of selective ligands. In the present study, utilizing a combined antisense-in vivo dialysis approach, we show that the D-5 subtype is the dopamine D1-like receptor involved in modulating hippocampal acetylcholine (ACh) release, a transmitter implicated in a variety of cognitive processes. This is one of the first evidence for a functional role for the D-5 receptor.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2000

Olfactory bulbectomy alters NMDA receptor levels in the rat prefrontal cortex.

Olfactory bulbectomized (OBX) rats show a variety of behavioral and biochemical deficits that parallel human depression. We investigated the expression of glutamate receptor subtypes in cortical and subcortical brain regions following bilateral olfactory bulbectomy in adult rats. Quantitative receptor autoradiography using [(125)I]MK-801 (NMDA receptor), [(3)H]AMPA (AMPA receptor), and [(3)H]kainate (kainate receptor) was performed on brain sections at 1-5 weeks following olfactory bulbectomy. Our results show an elevation of NMDA receptors in the medial prefrontal cortex within 1 week following bulbectomy, which persisted up to at least 5 weeks post-bulbectomy. Neither kainate nor AMPA receptors were altered in any brain region examined. The potential significance of these results is discussed in light of experimental findings supporting a role for NMDA receptors in the mechanism of action of antidepressant drugs and the pathophysiology of major depression.

Animals↗

PubMed2000

Insulin-like growth factor-1 (IGF-1): a neuroprotective trophic factor acting via the Akt kinase pathway.

Insulin-like growth factor-I (IGF-I) is a pleiotropic polypeptide with a wide range of actions in both central and peripheral nervous sytems. Over the past few years, we studied the trophic as well as neuromodulatory roles of IGF-I in the brain. Accumulated evidence indicates that IGF-I, apart from regulating growth and development, protects neurons against cell death induced by amyloidogenic derivatives, glucose or serum deprivation via the activation of intracellular pathways implicating phosphatidylinositide 3/Akt kinase, winged-helix family of transcription factor FKHRL1 phosphorylation or production of free radicals. The effects of IGF-I on neuroprotection, glucose metabolism and activity-dependent plasticity suggest the potential usefulness of this growth factor or related mimetics in the treatment of Alzheimer's disease and other neurodegenerative disorders.

Alzheimer Disease↗