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Biomedical subjects

Mark A Smith

Publications and source records attributed to Mark A Smith.

At least 19 recordsLinked to original sources
PubMed2007

Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses.

For nearly 20 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-beta, such that the amyloid cascade hypothesis has become the "null hypothesis." Indeed, amyloid-beta is, by the current definition of the disease, an obligate player in pathophysiology, is toxic to neurons in vitro, and, perhaps most compelling, is increased by all of the human genetic influences on the disease. Therefore, targeting amyloid-beta is the focus of considerable basic and therapeutic interest. However, an increasingly vocal group of investigators are arriving at an "alternate hypothesis" stating that amyloid-beta, while certainly involved in the disease, is not an initiating event but rather is secondary to other pathogenic events. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-beta is not as a harbinger of death but rather a protective response to neuronal insult. To determine which hypothesis relates best to Alzheimer disease requires a broader view of disease pathogenesis and is discussed herein.

Alzheimer Disease↗
PubMed2007

Temporal difference modeling of the blood-oxygen level dependent response during aversive conditioning in humans: effects of dopaminergic modulation.

BACKGROUND: The prediction error (PE) hypothesized by the temporal difference model has been shown to correlate with the phasic activity of dopamine neurons during reward learning and the blood-oxygen level dependent (BOLD) response during reward and aversive conditioning tasks. We hypothesized that dopamine would modulate the PE related signal in aversive conditioning and that haloperidol would reduce PE related activity, while an acute dose of amphetamine would increase PE related activity in the ventral striatum. METHODS: Healthy participants took an acute dose of amphetamine, haloperidol, or placebo. We used functional magnetic resonance imaging (fMRI) to measure the BOLD signal while they carried out an aversive conditioning task, using cutaneous electrical stimulation as the unconditioned stimulus (US) and yellow and blue circles as conditioned stimulus (CS+ and CS-, respectively). RESULTS: Prediction error related BOLD activity was seen only in the ventral striatum in the placebo subjects. The subjects given amphetamine showed a wider network of PE related BOLD activity, including the ventral striatum, globus pallidus, putamen, insula, anterior cingulate, and substantia nigra/ventral tegmental area. Haloperidol subjects did not show PE related activity in any of these regions. CONCLUSIONS: Our results provide the first demonstration that the modulation of dopamine transmission affects both the physiological correlates and PE related BOLD activity during aversive learning.

Adolescent↗
PubMed2006

The cell cycle hypothesis of Alzheimer's disease: suggestions for drug development.

The cell cycle of hypothesis of neural dysfunction in chronic neurodegenerative conditions such as Alzheimer's disease (AD) offers a unified approach to understanding both existing and novel strategies for drug development. At the present time, a ligand based approach is a pragmatic solution for identifying new chemical leads on which to base future discovery and optimisation. We have pursued a ligand based approach on the basis of public domain data to identify existing compounds capable of abrogating the cell cycle at the G0-G1 interface. Selected on this basis, irrespective of the tissue under study, we identified several classes of compounds as potential chemical leads. Of these compounds, at least ten have already been shown to be neuroprotective in animal models of acute neurodegeneration. Such compounds could form the basis of a screening exercise after development of suitable screening tools. Progressing of chemical leads through such an approach will be more efficient if future leads display relevant "drug-like" properties. Further, drug development in this arena should take account of the special concerns raised by targeting an elderly population. This will involve accounting for frequent polypharmacy in the aging population, and age-related alterations in physiology.

Aged↗
PubMed2006

LRRK2 in Parkinson's disease and dementia with Lewy bodies.

BACKGROUND: Mutations in LRRK2 encoding leucine-rich repeat kinase 2 are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease (PD). To examine whether LRRK2 is directly associated with neuropathology of PD and other related disorders, we analyzed LRRK2 in brains of patients affected by PD and dementia with Lewy bodies (DLB) using highly specific antibodies to LRRK2. RESULTS: We demonstrated that anti-LRRK2 antibodies strongly labelled brainstem and cortical Lewy bodies, the pathological hallmarks of PD and DLB, respectively. In addition, anti-LRRK2 also labelled brain vasculature, axons, and neuronal cell bodies. Interestingly, the immunocytochemical profile of LRRK2 varied with different antibodies depending upon specific antigenic sites along the LRRK2 protein. All anti-LRRK2 antibodies tested that were raised against various regions of LRRK2, were found to be immunoreactive to recombinant LRRK2 on Western blots. However, only the antibodies raised against the N-terminal and C-terminal regions of LRRK2, but not the regions containing folded protein domains, were positive in immunolabeling of Lewy bodies, suggesting a differential exposure of specific antigenic sites of LRRK2 on tissue sections. CONCLUSION: We conclude that LRRK2 is a component of Lewy bodies in both PD and DLB, and therefore plays an important role in the Lewy body formation and disease pathogenesis. Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of PD and related disorders.

Journal Article↗
PubMed2006

Alzheimer disease, the two-hit hypothesis: an update.

Given the relative modality of single-insult models to accurately reflect Alzheimer disease pathogenesis, based on studies on mitogenic and oxidative stress signaling pathways, we proposed a two-hit hypothesis 2 years ago stating that both oxidative stress and mitogenic dysregulation are necessary and sufficient to cause the disease and suggested that it may be a common mechanism for other neurodegenerative diseases as well (X. Zhu, A.K. Raina, G. Perry, M.A. Smith, Alzheimer's disease: the two-hit hypothesis, Lancet Neurol. 3 (2004) 219-226). Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in sporadic AD cases and therefore, in our opinion, strengthen the hypothesis, which will be the focus of this review.

Alzheimer Disease↗
PubMed2006

Aberrant localization of importin alpha1 in hippocampal neurons in Alzheimer disease.

Since many nuclear proteins are ectopically localized in the cytoplasm in the vulnerable neurons in Alzheimer disease (AD), we speculated that there is failure of the cytoplasmic-nuclear transport machinery in AD. In support of this notion, we found that importin alpha1, an essential component of cytoplasmic-nuclear transport, is abnormally accumulated in Hirano bodies in vulnerable hippocampal neurons in AD. These data suggest a hindrance in importin-mediated cytoplasmic-nuclear transport in AD.

Actins↗
PubMed2006

Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances.

The hypothalamic melanocortin system is crucial for the control of appetite and body weight. Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of energy homeostasis, with the MC4R having the major influence. It is generally thought that the main impact of the melanocortin system on hypothalamic circuits is external to the arcuate nucleus, and that any effect locally in the arcuate nucleus is inhibitory on proopiomelanocortin-expressing (POMC) neurons. In contrast, using current- and voltage-clamp recordings from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons and a separate arcuate neuronal population identified by the rat insulin 2 promoter (RIPCre) transgene expression. Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP), hyperpolarizes POMC and RIPCre neurons in the absence of melanocortin agonist, consistent with inverse agonism at the MC4R. A decreased transient outward (I(A)) potassium conductance, and to a lesser extent the inward rectifier (K(IR)) conductance, underlies neuronal depolarization, whereas an increase in I(A) mediates AgRP-induced hyperpolarization. Accordingly, POMC and RIPCre neurons may be targets for peptide transmitters that are possibly released locally from AgRP-expressing and POMC neurons in the arcuate nucleus, adding further previously unappreciated complexity to the arcuate system.

4-Aminopyridine↗
PubMed2006

Gonadotropins: a cohesive gender-based etiology of Alzheimer disease.

While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease.

Alzheimer Disease↗
PubMed2006

Neuronal cell cycle re-entry mediates Alzheimer disease-type changes.

Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G2/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies.

Alzheimer Disease↗
PubMed2006

Steroidogenic acute regulatory protein (StAR): evidence of gonadotropin-induced steroidogenesis in Alzheimer disease.

BACKGROUND: Alzheimer disease (AD) is clinically characterized by progressive memory loss, impairments in behavior, language and visual-spatial skills and ultimately, death. Epidemiological data reporting the predisposition of women to AD has led to a number of lines of evidence suggesting that age-related changes in hormones of the hypothalamic-pituitary-gonadal (HPG) axis following reproductive senescence, may contribute to the etiology of AD. Recent studies from our group and others have reported not only increases in circulating gonadotropins, namely luteinizing hormone (LH) in individuals with AD compared with control individuals, but also significant elevations of LH in vulnerable neuronal populations in individuals with AD compared to control cases as well as the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD. However, while LH is higher in AD patients, the downstream consequences of this are incompletely understood. To begin to examine this issue, here, we examined the expression levels of steroidogenic acute regulatory (StAR) protein, which regulates the first key event in steroidogenesis, namely, the transport of cholesterol into the mitochondria, and is regulated by LH through the cyclic AMP second messenger pathway, in AD and control brain tissue. RESULTS: Our data revealed that StAR protein was markedly increased in both the cytoplasm of hippocampal pyramidal neurons as well as in the cytoplasm of other non-neuronal cell types from AD brains when compared with age-matched controls. Importantly, and suggestive of a direct mechanistic link, StAR protein expression in AD brains colocalized with LH receptor expression. CONCLUSION: Therefore, our findings suggest that LH is not only able to bind to its receptor and induce potentially pathogenic signaling in AD, but also that steroidogenic pathways regulated by LH may play a role in AD.

Journal Article↗
PubMed2006

Increased expression of p130 in Alzheimer disease.

A number of recent findings support the notion of mechanistic parallels between Alzheimer disease (AD) and oncogenic processes, specifically, that neurons in AD, like cancer cells, display aberrant mitotic cell cycle re-entry. However, the mechanism that drives postmitotic neurons to reenter cell cycle remains elusive. In this study, we focused on the retinoblastoma-related protein p130 in AD. p130 is a transcriptional regulator that complexes with E2F4/5 in the nucleus and suppresses genes that regulate entry into the cell cycle. Interestingly, our results show that there are increases in p130 in cytoplasm of susceptible pyramidal neurons as well as neuroglia, often surrounding senile plaques, and within Hirano bodies in AD. By marked contrast, p130 is found at background levels in non-diseased, age-matched controls. Our data suggest that, despite its upregulation, the aberrant localization of p130 to the neuronal cytoplasm facilitates neuronal cell cycle re-entry in AD.

Aged↗
PubMed2006

The motor-impairing effects of GABA(A) and GABA(B) agonists in gamma-hydroxybutyrate (GHB)-treated rats: cross-tolerance to baclofen but not flunitrazepam.

gamma-Hydroxybutyrate (GHB) is believed to function as a neurotransmitter in the mammalian brain by binding to a GHB-specific binding site. In addition, GHB may also indirectly enhance the neuroinhibitory actions of gamma-aminobutyric acid (GABA) by converting to GABA at neuronal synapses. The purpose of the present study was to examine the effects of representative GABA(A) and GABA(B) receptor agonists in rats treated chronically with GHB. Using a rotorod apparatus, the motor-impairing effects of GHB, the indirect GABA(A) receptor agonist, flunitrazepam, and the direct GABA(B) receptor agonist, baclofen, were examined before, during and after chronic treatment with 1000 mg/kg GHB, b.i.d. Prior to chronic treatment, all three drugs produced dose-dependent decreases in motor performance at low (8 rpm) and high (32 rpm) rotational speeds. Chronic treatment with GHB significantly decreased the potency of baclofen at both speeds, but did not alter the potency of either GHB or flunitrazepam. Following termination of chronic treatment, the potency of baclofen increased significantly at both speeds and returned to that observed prior to chronic treatment. These data indicate that chronic treatment with GHB confers tolerance to a GABA(B) receptor agonist under conditions in which tolerance is not conferred to a GABA(A) receptor agonist. These findings are consistent with the in vivo behavioral profile of GHB, which reveals a greater role for GABA(B) receptors than for GABA(A) receptors in its behavioral effects.

Adjuvants, Anesthesia↗
PubMed2006

Malignant glioma progression and nitric oxide.

Glioblastoma multiforme, the most common of the malignant gliomas, carries a dismal prognosis in spite of the most aggressive therapy and recent advances in molecular pathways of glioma progression. Although it has received relatively little attention in the setting of malignant gliomas, nitric oxide metabolism may be intimately associated with the disease process. Interestingly, nitric oxide has both physiological roles (e.g., neurotransmitter-like activity, stimulation of cyclic GMP), and pathophysiological roles (e.g., neoplastic transformation, tumor neovascularization, induction of apoptosis, free radical damage). Moreover, whether nitric oxide is neuroprotective or neurotoxic in a given disease state, or whether it enhances or diminishes chemotherapeutic efficacy in malignant neoplasia, is unresolved. This review discusses the multifaceted activity of nitric oxide with particular reference to malignant gliomas.

Brain Neoplasms↗
PubMed2006

Nanoparticle iron chelators: a new therapeutic approach in Alzheimer disease and other neurologic disorders associated with trace metal imbalance.

Accumulating evidence suggests that oxidative stress may be a major etiologic factor in initiating and promoting neurodegeneration in Alzheimer disease. Contributing to this, there is a dyshomeostasis of metal ions in Alzheimer disease with abnormally high levels of redox-active metals, particularly iron, in affected areas of the brain. Although it is unclear whether metal excesses are the sole cause of oxidative stress and neurodegeneration or a by-product of neuronal loss, the finding that metal chelators can partially solubilize amyloid-beta deposits in Alzheimer disease suggests a promising therapeutic role for chelating agents. However, the blood-brain barrier and toxicity of known chelators limit their utility. In this study, we suggest that covalent conjugation of iron chelators with nanoparticles may help overcome the limitations in blood-brain barrier permeability of existing chelation therapy. Using in vitro studies, we have shown that a chelator-nanoparticle system and the chelator-nanoparticle system complexed with iron, when incubated with human plasma, preferentially adsorb apolipoprotein E and apolipoprotein A-I, that would facilitate transport into and out of the brain via mechanisms used for transporting low-density lipoprotein. Our studies suggest a unique approach, utilizing nanoparticles, to transport chelators and chelator-metal complexes in both directions across the blood-brain barrier, thus providing safer and more effective chelation treatment in Alzheimer disease and other neurodegenerative diseases.

Aged, 80 and over↗
PubMed2006

Chronic exercise decreases sensitivity to mu opioids in female rats: correlation with exercise output.

Aerobic exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e., pain) threshold in a naloxone-reversible manner. During chronic exercise, sensitivity to the antinociceptive effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross-tolerance to exogenously administered opioid agonists. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine if changes in opioid sensitivity during chronic exercise are correlated with exercise output. Eight female rats were obtained at weaning and housed in standard laboratory cages that did not permit any exercise beyond normal cage ambulation. Following 6 weeks under these conditions, opioids possessing a range of relative efficacies at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol) were examined in a warm-water, tail-withdrawal procedure. Under sedentary conditions, all opioids produced dose-dependent increases in tail-withdrawal latencies, and high levels of antinociception were observed for all drugs. Following these tests, rats were reassigned to exercise conditions and transferred to cages equipped with running wheels. Under these conditions, rats ran an average of 7154 rev/day (7869 m/day), with a range across rats from 4501 to 10,164 rev/day (4951-11,180 m/day). Sensitivity to all four opioids decreased significantly during the exercise period, resulting in 2- to 5-fold decreases in the potency of morphine, levorphanol and buprenorphine, and decreases in the effectiveness of buprenorphine and butorphanol. When rats were returned to sedentary conditions, sensitivity to all four opioids increased significantly and returned to that observed prior to the exercise period. For all drugs, there was a positive correlation between exercise output and changes in opioid sensitivity between sedentary and exercise conditions. These data suggest that chronic exercise decreases sensitivity to mu opioids in female rats, and that these changes in sensitivity are positively correlated with exercise output.

Analgesics↗
PubMed2006

PKC inhibition is involved in trichosanthin-induced apoptosis in human chronic myeloid leukemia cell line K562.

Trichosanthin (TCS), a type I ribosome-inactivating protein, induces cell death in various cell types including several tumor cell lines. However, the mechanism remains largely uncharacterized. In this study, we investigated the possible mechanism underlying its cytotoxicity by using human chronic myeloid leukemia cell line K562. We found that TCS induced apoptosis in K562 cells in a time- and concentration-dependent manner and can be blocked by caspase-3 inhibitors. Interestingly, TCS treatment induced a transient elevation in intracellular calcium concentration and a slow increase in reactive oxygen species production, while calcium chelators and antioxidants had no obvious effect on TCS-induced apoptosis, suggesting that calcium changes and reactive oxygen species may not be involved in TCS-mediated apoptosis in K562 cells. Instead we found that TCS partly inhibited PKC activity. Indeed, the PKC activator, PMA, inhibited while the PKC inhibitor, calphostin c, enhanced TCS-induced apoptosis. These PKC modulators had similar effects on TCS-induced cleavage of caspase-3, and caspase-3 inhibitors prevented calphostin c-enhanced apoptosis induced by TCS. In summary, we conclude that TCS induces apoptosis in K562 cells partly via PKC inhibition and caspase-3 activation.

Apoptosis↗