Biomedical subjects

Lechoslaw Turski

Publications and source records attributed to Lechoslaw Turski.

9 recordsLinked to original sources

PubMed2005

NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth.

Glutamate antagonists limit the growth of human cancers in vitro. The mechanism of anticancer action of NMDA antagonists is not known, however. In this article, we report that the NMDA antagonist dizocilpine inhibits the extracellular signal-regulated kinase 1/2 pathway, an intracellular signaling cascade that is activated by growth factors and controls the proliferation of cancer cells. Dizocilpine reduces the phosphorylation of cAMP-responsive element binding protein, suppresses the expression of cyclin D1, up-regulates the cell cycle regulators and tumor suppressor proteins p21 and p53, and increases the number of lung adenocarcinoma cells in the G(2) and S phases of the cell cycle. Silencing of the tumor suppressor protein p21 abolishes antiproliferative action of dizocilpine. Consistent with inhibition of the extracellular signal-regulated kinase 1/2-signaling cascade, dizocilpine reverses the stimulation of proliferation induced by epidermal, insulin, and basic fibroblast growth factors in lung adenocarcinoma cells. Furthermore, dizocilpine prolongs the survival of mice with metastatic lung adenocarcinoma and slows the growth of neuroblastoma and rhabdomyosarcoma in mice. These findings reveal the mechanism of antiproliferative action of dizocilpine and indicate that it may be useful in the therapy of human cancers.

Antineoplastic Agents↗

PubMed2005

Novel alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonists of 2,3-benzodiazepine type: chemical synthesis, in vitro characterization, and in vivo prevention of acute neurodegeneration.

Under pathophysiological conditions, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor activation is considered to play a key role in several disorders of the central nervous system. In the search for AMPA receptor antagonists, the synthesis and pharmacological characterization of a series of novel compounds that are structurally related to GYKI 52466 (1), a well-known selective noncompetitive AMPA receptor antagonist, was performed. In vitro, 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638, 14a) antagonized the kainate-induced currents in cultured hippocampal neurons with an IC(50) of 3.4 microM in a noncompetitive fashion. When tested in a clinically predictive rat model of acute ischemic stroke, this noncompetitive AMPA receptor antagonist significantly reduced brain infarction, indicating that it is neuroprotective after permanent focal cerebral ischemia.

Acute Disease↗

PubMed2005

Late-onset motoneuron disease caused by a functionally modified AMPA receptor subunit.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the central nervous system in middle and old age that leads to progressive loss of spinal motoneurons. Transgenic mice overexpressing mutated human Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) reproduce clinical features of the familial form of ALS. However, changes in SOD1 activity do not correlate with severity of motor decline in sporadic cases, indicating that targets unrelated to superoxide metabolism contribute to the pathogenesis of the disease. We show here that transgenic expression in mice of GluR-B(N)-containing L-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors with increased Ca(2+) permeability leads to late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progresses over the entire lifespan but manifests clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerates disease progression, aggravates the severity of motor decline, and decreases survival. These observations link persistently elevated Ca(2+) influx through AMPA channels with progressive motor decline and late-onset degeneration of spinal motoneurons, indicating that functionally altered AMPA channels may be causally related to pathogenesis of sporadic ALS in humans.

Amyotrophic Lateral Sclerosis↗

PubMed2005

Mechanisms of disease: motoneuron disease aggravated by transgenic expression of a functionally modified AMPA receptor subunit.

To reveal whether increased Ca2+ permeability of glutamate AMPA channels triggered by the transgene for GluR-B(N) induces decline in motor functions and neurodegeneration in the spinal cord, we evaluated growth, motor coordination, and spinal reflexes in transgenic GluR-B(N) and wild-type (wt) mice. To reveal whether the transgenic GluR-B(N) expression aggravates the course of motoneuron disease in SOD1 mice, we mated heterozygous GluR-B(N) and SOD1 [C57BL6Ico-TgN(hSOD1-G93A)1Gur] mice to generate double-transgenic progeny. The phenotypic sequelae in mice carrying mutations were evaluated by monitoring growth, motor coordination, and survival. Neuronal degeneration was assessed by morphological and stereological analysis of spinal cord and brain. We found that transgenic expression in mice of GluR-B(N)-containing glutamate AMPA receptors with increased Ca2+ permeability leads to a late-onset degeneration of neurons in the spinal cord and decline of motor functions. Neuronal death progressed over the entire life span, but manifested clinically in late adulthood, resembling the course of a slow neurodegenerative disorder. Additional transgenic expression of mutated human SOD1 accelerated disease progression, aggravated severity of motor decline, and decreased survival. These observations reveal that moderate, but persistently elevated Ca2+ influx via glutamate AMPA channels causes degeneration of spinal motoneurons and motor decline over the span of life. These features resemble the course of sporadic amyotrophic lateral sclerosis (ALS) in humans and suggest that modified function of glutamate AMPA channels may be causally linked to pathogenesis of ALS.

Animals↗

PubMed2003

Multiple sclerosis and glutamate.

Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune-mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti-inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non-competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short-term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.

Animals↗

PubMed2002

Glutamate antagonists limit tumor growth.

The management of malignancies in humans constitutes a major challenge for contemporary medicine. Despite progress in chemotherapy, bone marrow transplantation, surgical measures, and radiation technologies, and in immunological and immunomodulatory approaches, humans continue to succumb to cancer due to tumor recurrence and metastatic disease. The excitatory neurotransmitter glutamate, which regulates proliferation and migration of neuronal progenitors and immature neurons during the development of the mammalian nervous system, is present in peripheral cancers. Since both neuronal progenitors and tumor cells possess propensity to proliferate and to migrate, and since glutamate and glutamate receptors are known to modify these phenomena in the nervous system, we proceeded to investigate the possible influence of glutamate antagonists on the proliferation and migration of tumor cells. We found and recently reported that glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonists inhibit the proliferation of human colon adenocarcinoma, astrocytoma, breast and lung carcinoma, and neuroblastoma cells in vitro. The antiproliferative effect of glutamate antagonists is Ca(2+)-dependent and results from decreased cell division and increased cell death. Glutamate antagonists produce morphological alterations in tumor cells, which consist of reduced membrane ruffling and pseudopodial protrusions, and decrease their motility and invasive growth. Furthermore, glutamate antagonists enhance in vitro cytostatic and cytotoxic effects of common chemotherapeutic agents used in cancer therapy. These findings demonstrate the anticancer potential of glutamate antagonists and suggest that they may be used as an adjunctive measure in the treatment of cancer.

Animals↗

PubMed2002

Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?

Glutamate N-methyl-D-aspartate (NMDA) receptor antagonists (competitive receptor antagonists, ion channel blockers, and glycine antagonists)--such as selfotel, aptiganel, eliprodil, licostinel and gavestinel--failed to show efficacy in clinical trials of stroke or traumatic brain injury. This failure has been attributed to the deficient properties of the molecules that entered human trials and to inappropriate design of clinical studies. In this article we hypothesise that glutamate may be involved in the acute neurodestructive phase that occurs immediately after traumatic or ischaemic injury (excitotoxicity), but that, after this period, it assumes its normal physiological functions, which include promotion of neuronal survival. We propose that NMDA receptor antagonists failed stroke and traumatic brain injury trials in human beings because blockade of synaptic transmission mediated by NMDA receptors hinders neuronal survival.

Brain Injuries↗

PubMed2000

Phosphonate quinoxalinedione AMPA antagonists.

In the Western world, over 350,000 deaths and $30 billion in medical costs are attributed annually to stroke. Head and spinal cord trauma cause an estimated 250,000 deaths annually and result in medical costs of $15 billion. Although stroke and head/spinal cord trauma are leading causes of disability and death in humans, no adequate neuroprotective treatment is available. Glutamate antagonists derived from the quinoxa-linedione scaffold are as drug candidates for neuroprotection in stroke and trauma. Quinoxalinedione derivatives such as 2,3-dihydroxy-6- nitro-7-sulfamoylbenzo(f)quinoxaline and 6-(1H-imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxalinedione failed clinical trials because of insolu-bility and resulting nephrotoxicity. Introduction of a phosphonate group into the quinoxalinedione skeleton improves solubility and leaves potency for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor unchanged. Phosphonate quinoxalinedione derivatives ZK202000 and ZK200775 protected rodent brain against sequelae of permanent occlusion of the middle cerebral artery and head trauma. No major deleterious effects on motor coordination, cardiovascular, or respiratory systems were detected in doses required for neuroprotection. No psychotomimetic and no neurotoxic side effects, typical for N-methyl-D-aspartate antagonists, were observed following treatment with phosphonate quinoxalinediones.

Journal Article↗

PubMed1998

Tolerance to and Dependence on Alprazolam are Due to Changes in GABAa Receptor Function and Are Independent of Exposure to Experimental Set-up.

The development of tolerance to and dependence on BDZs was investigated by monitoring locomotor activity in mice. Alprazolam (6 mg/kg twice daily s.c.) or solvent were administered over 12 days. The treatment schedule at least 50% BDZ receptor occupancy throughout treatment. Receptor occupancy half-lives were determined to be 2.6 hrs and 4.8 hrs. after cessation of 4 and 12 days of alprazolam administration, respectively. To assess if the tolerance to and dependence on alprazolam were due to repeated exposure of mice to the experimental set-up, some groups of mice were tested repeatedly, while other groups were subjected only to a single exposure. The observed locomotor activity, measured as horizontal activity and total distance travelled, indicated that the development of tolerance and of withdrawal symptoms to alprazolam is not related to repeated exposure of the mice to the experimental set-up, but is due to changes in function of the GABAa receptor.

Journal Article↗