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Ahmet Hoke

Publications and source records attributed to Ahmet Hoke.

5 recordsLinked to original sources
PubMed2003

FK506 is neuroprotective in a model of antiretroviral toxic neuropathy.

Antiretroviral toxic neuropathy is the most common neurological complication of human immunodeficiency virus infection. This painful neuropathy not only affects the quality of life of human immunodeficiency virus-infected patients but also severely limits viral suppression strategies. We have developed an in vitro model of this toxic neuropathy to better understand the mechanism of neurotoxicity and to test potential neuroprotective compounds. We show that among the dideoxynucleosides, ddC appears to be the most neurotoxic, followed by ddI and then d4T. This reflects their potency in causing neuropathy. AZT, which does not cause a peripheral neuropathy in patients, does not cause significant neurotoxicity in our model. Furthermore, in this model, we show that the immunophilin ligand FK506 but not cyclosporin A prevents the development of neurotoxicity by ddC, as judged by amelioration of ddC-induced "neuritic pruning," neuronal mitochondrial depolarization, and neuronal necrotic death. This finding suggests a calcineurin-independent mechanism of neuroprotection. As calcineurin inhibition underlies the immunosuppressive properties of these clinically used immunophilin ligands, this holds promise for the neuroprotective efficacy of nonimmunosuppressive analogs of FK506 in the prevention or treatment of antiretroviral toxic neuropathy.

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PubMed2003

Schwann cell chemokine receptors mediate HIV-1 gp120 toxicity to sensory neurons.

Human immunodeficiency virus (HIV)-associated sensory neuropathy (HIV-SN) is the most common neurological complication of HIV infection. Currently, the pathogenesis of HIV-SN is unknown. Because there is no convincing evidence of neuronal infection, HIV neurotoxicity is likely to be effected either by secreted viral proteins such as the envelope glycoprotein gp120 or by neurotoxic cytokines released from infected/activated glial cells. We describe a model of gp120 toxicity to primary sensory neurons, in which gp120 induces neuritic degeneration and neuronal apoptosis. We show that Schwann cells, the cells that ensheath peripheral nerve axons, and which traditionally have been viewed as having a passive, supporting role, mediate this neurotoxicity. Ligation of the chemokine receptor CXCR4 on Schwann cells by gp120 resulted in the release of RANTES, which induced dorsal root ganglion neurons to produce tumor necrosis factor-alpha and subsequent TNFR1-mediated neurotoxicity in an autocrine fashion. This newly described Schwann cell-neuron interaction may be pathogenically relevant not only in HIV-SN but also in other peripheral neuropathies.

Animals↗
PubMed2003

Designing, testing, and validating a focused stem cell microarray for characterization of neural stem cells and progenitor cells.

Fetal neural stem cells (NSCs) have received great attention not only for their roles in normal development but also for their potential use in the treatment of neurodegenerative disorders. To develop a robust method of assessing the state of stem cells, we have designed, tested, and validated a rodent NSC array. This array consists of 260 genes that include cell type-specific markers for embryonic stem (ES) cells and neural progenitor cells as well as growth factors, cell cycle-related genes, and extracellular matrix molecules known to regulate NSC biology. The 500-bp polymerase chain reaction products amplified and validated by using gene-specific primers were arrayed along with positive controls. Blanks were included for quality control, and some genes were arrayed in duplicate. No cross-hybridization was detected. The quality of the arrays and their sensitivity were also examined by using probes prepared by conventional reverse transcriptase or by using amplified probes prepared by linear polymerase replication (LPR). Both methods showed good reproducibility, and probes prepared by LPR labeling appeared to detect expression of a larger proportion of expressed genes. Expression detected by either method could be verified by RT-PCR with high reproducibility. Using these stem cell chips, we have profiled liver, ES, and neural cells. The cell types could be readily distinguished from each other. Nine markers specific to mouse ES cells and 17 markers found in neural cells were verified as robust markers of the stem cell state. Thus, this focused neural stem array provides a convenient and useful tool for detection and assessment of NSCs and progenitor cells and can reliably distinguish them from other cell populations.

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