Mechanisms of toxic injury in the peripheral nervous system: neuropathologic considerations.
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The anatomical distribution and organization of the peripheral nervous system as well as its frequent ability to reflect neurotoxic injury make it useful for the study of nerve fiber and ganglionic lesions. Contemporary neuropathologic techniques provide sections with excellent light-microscopic resolution for use in making such assessments. The histopathologist examining such peripheral nerve samples may see several patterns of neurotoxic injury. Most common are axonopathies, conditions in which axonal alterations are noted; these axonopathies often progress toward the Wallerian-like degeneration of affected fibers. These are usually more severe in distal regions of the neurite, and they affect both peripheral and central fibers. Examples of such distal axonopathies are organophosphorous ester-induced delayed neuropathy, hexacarbon neuropathy, and p-bromophenylacetylurea intoxication. These axonopathies may have varying pathologic features and sometimes have incompletely understood toxic mechanisms. In such neuropathies with fiber degeneration, peripheral nerve axons may regenerate, which can complicate pathologic interpretation of neurotoxicity. On occasion neurotoxins elicit more severe injury in proximal regions of the fiber (not included in this review). Axonal pathology is also a feature of the neuronopathies, toxic states in which the primary injuries are found in neuronal cell bodies. This is exemplified by pyridoxine neurotoxicity, where there is sublethal or lethal damage to larger cytons in the sensory ganglia, with failure of such neurons to maintain their axons. Lastly, one may encounter myelinopathies, conditions in which the toxic effect is on the myelin-forming cell or sheath. An example of this is tellurium intoxication, where demyelination noted in young animals is coincident with toxin-induced interference of cholesterol synthesis by Schwann cells. In this paper, the above-noted examples of toxic neuropathy are discussed, with emphasis on mechanistic and morphologic considerations. (+info)
Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.
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PURPOSE: Little progress has been made in the treatment of adult high-grade gliomas over the last two decades, thus necessitating a search for novel therapeutic strategies. Malignant gliomas are vascular or angiogenic tumors, which leads to the supposition that angiogenesis inhibition may represent a potentially promising strategy in the treatment of these tumors. We present the results of a phase II trial of thalidomide, a putative inhibitor of angiogenesis, in the treatment of adults with previously irradiated, recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of anaplastic mixed glioma, anaplastic astrocytoma, or glioblastoma multiforme who had radiographic demonstration of tumor progression after standard external-beam radiotherapy with or without chemotherapy were eligible. Patients were initially treated with thalidomide 800 mg/d with increases in dose by 200 mg/d every 2 weeks until a final daily dose of 1,200 mg was achieved. Patients were evaluated every 8 weeks for response by both clinical and radiographic criteria. RESULTS: A total of 39 patients were accrued, with 36 patients being assessable for both toxicity and response. Thalidomide was well tolerated, with constipation and sedation being the major toxicities. One patient developed a grade 2 peripheral neuropathy after treatment with thalidomide for nearly a year. There were two objective radiographic partial responses (6%), two minor responses (6%), and 12 patients with stable disease (33%). Eight patients were alive more than 1 year after starting thalidomide, although almost all with tumor progression. Changes in serum levels of basic fibroblastic growth factor (bFGF) were correlated with time to tumor progression and overall survival. CONCLUSION: Thalidomide is a generally well-tolerated drug that may have antitumor activity in a minority of patients with recurrent high-grade gliomas. Future studies will better define the usefulness of thalidomide in newly diagnosed patients with malignant gliomas and in combination with radiotherapy and chemotherapy. Additionally, studies will be needed to confirm the potential utility of changes in serum bFGF as a marker of antiangiogenic activity and/or glioma growth. (+info)
Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer.
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PURPOSE: To determine the maximum-tolerated dose, toxicities, and pharmacokinetic profile of the farnesyl protein transferase inhibitor R115777 when administered orally bid for 5 days every 2 weeks. PATIENTS AND METHODS: Twenty-seven patients with a median age of 58 years received 85 cycles of R115777 using an intrapatient and interpatient dose escalation schema. Drug was administered orally at escalating doses as a solution (25 to 850 mg bid) or as pellet capsules (500 to 1300 mg bid). Pharmacokinetics were assessed after the first dose and the last dose administered during cycle 1. RESULTS: Dose-limiting toxicity of grade 3 neuropathy was observed in one patient and grade 2 fatigue (decrease in two performance status levels) was seen in four of six patients treated with 1,300 mg bid. The most frequent clinical grade 2 or 3 adverse events in any cycle included nausea, vomiting, headache, fatigue, anemia, and hypotension. Myelosuppression was mild and infrequent. Peak plasma concentrations of R115777 were achieved within 0.5 to 4 hours after oral drug administration. The elimination of R115777 from plasma was biphasic, with sequential half-lives of about 5 hours and 16 hours. There was little drug accumulation after bid dosing, and steady-state concentrations were achieved within 2 to 3 days. The pharmacokinetics were dose proportional in the 25 to 325 mg/dose range for the oral solution. Urinary excretion of unchanged R115777 was less than 0.1% of the oral dose. One patient with metastatic colon cancer treated at the 500-mg bid dose had a 46% decrease in carcinoembryonic antigen levels, improvement in cough, and radiographically stable disease for 5 months. CONCLUSION: R115777 is bioavailable after oral administration and has an acceptable toxicity profile. Based upon pharmacokinetic data, the recommended dose for phase II trials is 500 mg orally bid (total daily dose, 1, 000 mg) for 5 consecutive days followed by 9 days of rest. Studies of continuous dosing and studies of R115777 in combination with chemotherapy are ongoing. (+info)
Cholecystokinin-8 enhances nerve growth factor synthesis and promotes recovery of capsaicin-induced sensory deficit.
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Alterations of nerve growth factor (NGF) expression have been demonstrated during peripheral nerve disease and the impaired expression or synthesis and transportation of NGF has been correlated with the pathogenesis of several peripheral neuropathies. Since exogenous NGF administration seems to cause undesired side-effects, therapeutical strategies based on the regulation of endogenous synthesis of NGF could prove useful in the clinical treatment of these disorders. The aim of the present study was to analyse the effects of exogenous peripheral administration of the neuropeptide cholecystokinin-8 (CCK-8) on endogenous NGF synthesis, NGF mRNA and distribution of peripheral neuropeptides which are known to be regulated by this neurotrophin. To address these questions we studied the effects of capsaicin (CAPS) before and after the administration of CCK-8 on NGF levels, NGF mRNA expression and localization, and the concentration of substance P (SP) and calcitonin gene-related peptide (CGRP) in peripheral tissue These studies demonstrate that administration of the CCK-8 induces an increase of NGF protein and mRNA in peripheral tissue. NGF level in paw skin of CAPS/CCK-8-treated mice is 3 fold higher than in controls (1241+/-110 pg gr(-1) of tissue wet weight versus 414+/-110 pg gr(-1) of controls) and nearly 6 fold higher than in CAPS-treated mice (1241+/-110 pg gr(-1) versus 248+/-27 pg gr(-1)). The increase of NGF is correlated with the recovery of impaired nocifensive behaviour and with an overexpression of SP and CGRP. The evidence that CCK-8 promotes the recovery of sensory deficits suggests a potential clinical use for this neuropeptide in peripheral neuropathies. (+info)
Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering alpha(1A) Ca(2+) channel mutation.
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Neurotransmitter release at many synapses is regulated by P/Q-type Ca(2+) channels containing the alpha(1A) pore-forming subunit. Mutations in alpha(1A) cause cerebral disorders including familial hemiplegic migraine (FHM) and ataxia in humans. Tottering (tg) alpha(1A) mutant mice display ataxia and epilepsy. It is not known whether alpha(1A) mutations induce impairment of synaptic function, which could underlie the symptoms of these cerebral disorders. To assess whether alpha(1A) mutations influence neurotransmitter release, we studied P-type Ca(2+) channel-mediated acetylcholine (ACh) release at tg neuromuscular junctions (NMJs) with micro-electrode measurements of synaptic potentials. We found a Ca(2+)-, Mg(2+)- and K(+)-dependent increase of spontaneous ACh release at both homo- and heterozygote tg NMJs. Furthermore, there was increased run-down of high-rate evoked release at homozygous tg NMJs. In isotonic contraction experiments this led to block of synaptic transmission at lower concentrations of the ACh antagonist tubocurarine than were needed in wild-type muscles. Our results suggest that in tg motor nerve terminals there is increased influx of Ca(2+) under resting conditions. This study shows that functional consequences of alpha(1A) mutations causing cerebral disorders can be characterized at the NMJ. (+info)
Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats.
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1. The function and role of P2X receptors in the spinal transmission of nociception was investigated using the selective P2X receptor agonists, alpha,beta-methylene ATP (alpha,beta-me ATP) and beta, gamma-methylene-L-ATP (beta,gamma-me-L-ATP) and the P2X receptor antagonists pyridoxal-phosphate-6-azophenyl-2',4'-disulphonate (PPADS) and suramin. 2. Intrathecal administration of 5 and 50 microg of beta,gamma-me-L-ATP produced a significant facilitation of the C-fibre evoked response and a tendency towards increased excitability of the post-discharge, but not Abeta-fibre evoked response of dorsal horn neurones recorded in normal animals. Administration of similar doses of alpha,beta-me ATP did not produce an overall change in the response of the neuronal population. 3. Peripheral administration of 20 microg of these agonists into the paw of the rat evoked firing in the dorsal horn neurones. 4. Intrathecal administration of the antagonists, suramin (50 and 500 microg) and PPADS (5, 50 and 500 microg), to normal animals and to animals with a model of neuropathy induced by spinal nerve ligation did not alter the evoked neuronal responses. In contrast, intrathecal administration of 500 microg of suramin to animals 3 h after the induction of carrageenan inflammation produced a significant inhibition of the C-fibre evoked response of the neurones. Similar inhibitions were also seen following high doses of intrathecal PPADS, although this did not reach significance. 5. These results suggest that spinal P2X receptors may play a role in the modulation of spinal nociceptive transmission following the development of inflammation, but that these receptors play at most a minor role in spinal nociceptive processing in normal and neuropathic animals. (+info)
P(0) glycoprotein overexpression causes congenital hypomyelination of peripheral nerves.
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We show that normal peripheral nerve myelination depends on strict dosage of the most abundantly expressed myelin gene, myelin protein zero (Mpz). Transgenic mice containing extra copies of Mpz manifested a dose-dependent, dysmyelinating neuropathy, ranging from transient perinatal hypomyelination to arrested myelination and impaired sorting of axons by Schwann cells. Myelination was restored by breeding the transgene into the Mpz-null background, demonstrating that dysmyelination does not result from a structural alteration or Schwann cell-extrinsic effect of the transgenic P(0) glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P(0) protein was detected only in nerves of low copy-number animals. Breeding experiments placed the threshold for dysmyelination between 30 and 80% Mpz overexpression. These data reveal new points in nerve development at which Schwann cells are susceptible to increased gene dosage, and suggest a novel basis for hereditary neuropathy. (+info)
A dual role of erbB2 in myelination and in expansion of the schwann cell precursor pool.
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Neuregulin-1 provides an important axonally derived signal for the survival and growth of developing Schwann cells, which is transmitted by the ErbB2/ErbB3 receptor tyrosine kinases. Null mutations of the neuregulin-1, erbB2, or erbB3 mouse genes cause severe deficits in early Schwann cell development. Here, we employ Cre-loxP technology to introduce erbB2 mutations late in Schwann cell development, using a Krox20-cre allele. Cre-mediated erbB2 ablation occurs perinatally in peripheral nerves, but already at E11 within spinal roots. The mutant mice exhibit a widespread peripheral neuropathy characterized by abnormally thin myelin sheaths, containing fewer myelin wraps. In addition, in spinal roots the Schwann cell precursor pool is not correctly established. Thus, the Neuregulin signaling system functions during multiple stages of Schwann cell development and is essential for correct myelination. The thickness of the myelin sheath is determined by the axon diameter, and we suggest that trophic signals provided by the nerve determine the number of times a Schwann cell wraps an axon. (+info)