Differential effects of paclitaxel treatment on cognitive functioning and mechanical sensitivity

Treatment for cancer has been indicated to negatively impact the quality of life for patients. Specifically, chemotherapy has been associated with fatigue, nausea, and peripheral neuropathy. More recently, chemotherapy has been found to be related to cognitive impairment in various domains including working memory, information processing speed, and visual attention. At this time, the mechanisms underlying cognitive impairment are not understood, and there is currently no treatment for this condition. The purpose of this study was to examine the development of chemotherapy-induced cognitive impairments and symptoms of peripheral neuropathy. While receiving the chemotherapeutic agent Taxol, animals were tested daily in the Five Choice Serial Reaction Time Task (5CSRTT), a task which requires animals to respond to a visually presented stimulus in order to obtain reinforcement. In addition, animals were tested for the development of peripheral neuropathy, measured by changes in sensitivity to mechanical stimulation. The results indicate Taxol treated animals developed mechanical sensitivity within 24 h after the first injection of chemotherapy. However, relative to control animals, Taxol treated animals did not exhibit alterations in cognitive function in the 5CSRTT. These differential findings may provide interesting insight into the mechanisms underlying chemotherapy-related cognitive impairment.     

Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat

The development of painful peripheral neuropathy is a dose-limiting side effect of numerous cancer chemotherapeutic agents. The present study utilized a rodent model of vincristine-induced neuropathy to determine whether a glial modulating agent, propentofylline, could attenuate vincristine-induced mechanical allodynia. Intravenous vincristine administered on days 1 through 5 and days 8 through 11 produced mechanical allodynia using 2 and 12 g von Frey filaments. Lumbar spinal cord from animals on day 15 expressed mild bilateral microglial and astrocytic activation as compared to saline-treated animals. Daily intraperitoneal propentofylline at 10 mg/kg attenuated mechanical allodynia induced by vincristine administration. In addition, propentofylline was found to decrease spinal microglial and astrocytic activation on day 15. These data suggest that central glial cells may play an important role in the development of painful neuropathy following vincristine administration.     

A differential involvement of the shell and core subterritories of the nucleus accumbens of rats in attentional processes

The nucleus accumbens comprises of two anatomically distinct subterritories: an inner core and an outer shell region. The distinct pattern of the core and shell input and output targets suggests that these two regions may mediate different behavioral processes. Using N-methyl-D-aspartate excitotoxic lesions in either the core or shell region, we investigated whether we can dissociate functionally these two subterritories. N-Methyl-D-aspartate-lesioned, sham-lesioned and non-operated animals were tested for locomotor activity in an open field and in two behavioral paradigms known to evaluate attentional deficits, namely the pre-pulse inhibition of the acoustic startle reflex and latent inhibition, measured in a two-way active avoidance paradigm. The shell-lesioned animals showed a small but significant hyperactivity in the open field when compared to the core-lesioned and to control animals. In the pre-pulse inhibition paradigm, core-lesioned animals demonstrated reduced pre-pulse inhibition to the two high pre-pulse intensities (80 dB[A], 84 dB[A]). In the active avoidance paradigm, whereas no lesion effects were detected in the non-pre-exposed groups, clear attenuation of latent inhibition was found in the shell-lesioned rats, in comparison to both core-lesioned and control rats, due to improved avoidance performance of the shell-pre-exposed group.From these results we suggest that the two subterritories of the nucleus accumbens are differentially involved in attention-related processes: the core lesion leads to significant disruption of pre-pulse inhibition while the shell lesion leads to heightened activity and significant attenuation of latent inhibition.     

Influence of peripheral nerve injury on response properties of locus coeruleus neurons and coeruleospinal antinociception in the rat

Noradrenergic locus coeruleus (LC) is involved in pain regulation. We studied whether response properties of LC neurons or coeruleospinal antinociception are changed 10-14 days following development of experimental neuropathy. Experiments were performed in spinal nerve-ligated, sham-operated and unoperated male rats under sodium pentobarbital anesthesia. Recordings of LC neurons indicated that responses evoked by noxious somatic stimulation were enhanced in nerve-injured animals, while the effects of nerve injury on spontaneous activity or the response to noxious visceral stimulation were not significant. Microinjection of glutamate into the central nucleus of the amygdala produced a dose-related inhibition of the discharge rate of LC neurons in nerve-injured animals but no significant effect on discharge rates in control groups. Assessment of the heat-induced hind limb withdrawal latency indicated that spinal antinociception induced by electrical stimulation of the LC was significantly weaker in nerve-injured than control animals. The results indicate that peripheral neuropathy induces bidirectional changes in coeruleospinal inhibition of pain. Increased responses of LC neurons to noxious somatic stimulation are likely to promote feedback inhibition of neuropathic hypersensitivity, while the enhanced inhibition of the LC from the amygdala is likely to suppress noradrenergic pain inhibition and promote neuropathic pain. It is proposed that the decreased spinal antinociception induced by direct stimulation of the LC may be explained by pronociceptive changes in the non-noradrenergic systems previously described in peripheral neuropathy. Furthermore, we propose the hypothesis that emotions processed by the amygdala enhance pain due to increased inhibition of the LC in peripheral neuropathy.     

Pregabalin in Chemotherapy Induced Neuropathic Pain

Chemotherapeutic agents belonging to vinca alkaloids, taxanes, and antitubulins produce peripheral neuropathy for which there is no validated treatment. Pregabalin, a gamma-aminobutyric acid analog, is known to inhibit theα2δ subunit of the voltage-gated calcium channel. Earlier studies and case reports have shown pregabalin to be effective in treating neuropathic pain. We present a case series of patients with chemotherapy-induced peripheral neuropathy who were successfully treated with pregabalin with reduction in the hyperalgesia, allodynia, and improvement in the quality of life.     

Peripheral neuropathy and anti-MAG antibodies

Peripheral neuropathy has been associated with monoclonal gammopathy in patients with Waldenstrom's macroglobulinemia, myeloma, B-cell lymphoma, and nonmalignant plasma cell dyscrasia. The neuropathy in these patients is heterogeneous and may be demyelinating or axonal, and sensory-motor or pure motor. The cause of neuropathy in many patients is unknown, but there is increasing evidence that in some cases it may be caused by autoantibody activity of M-proteins that bind to peripheral nerve antigens. Significant advances have been made in characterizing the autoantibody activity of M-proteins and correlating antigenic specificity with the type of neuropathy present, in elucidating the effector mechanisms responsible for causing nerve injury, and in understanding the causes for the aberrant immune response. This article reviews the recent advances made in this field and discusses their implications for the clinical evaluation and management of patients with peripheral neuropathy and monoclonal gammopathy.     

Clinical usefulness of vinca alkaloid slow infusion in the treatment of chronic refractory idiopathic thrombocytopenic purpura: a multicenter cooperative study

Thirty-eight patients with chronic refractory idiopathic thrombocytopenic purpura (ITP) were treated with weekly slow infusions of vincristine (0.02 to 0.04 mg/kg) or vinblastine (0.1 to 0.2 mg/kg). Twenty-two patients showed good to excellent responses after one to eight infusions. These responses were generally short, and lasted only in six patients after discontinuance of the therapy. The efficacy was comparable between vincristine and vinblastine. Neither the age, sex, duration of the disease, prior splenectomy nor combined use of adrenocortical steroids was likely to have influenced the therapeutic effect. Side effects such as peripheral neuropathy, alopecia, gastrointestinal symptoms and leukopenia occurred in 34 patients, and necessitated discontinuance of the therapy in eight patients. Slow infusions of vinca alkaloids can be an effective means of inducing platelet response in patients with chronic refractory ITP, but frequent side effects limit its clinical usefulness.     

Effects of antimetastatic,antiinvasive and cytotoxic agents on the growth and spread of transplantable leukemias in mice

The effects of cytotoxic (cyclophosphamide, CCNU, GANU), antiinvasive (vincristine, vinblastine) and antimetastatic (ICRF-159, DM-COOK) agents have been compared in mice-bearing P388 and L1210 leukemias, and TLX5 lymphoma. The drugs tested increase the survival time of the treated mice in a manner consistent with a cytotoxic action in the case of cyclophosphamide, CCNU, GANU, vincristine and vinblastine. Leukemic infiltration of the brain after i.p. tumor implantation has been determined by bioassay of this organ, and is reduced by treatment with all of the drugs tested, with the exception of ICRF-159. DM-COOK appears to increase the life-span of the treated animals by the inhibition of leukemic spread rather than by a cytotoxic action. The marked cytotoxicity of vincristine and vinblastine is sufficient to account for failure to detect any antimetastatic effects of these agents. The lack of antidisseminative effect observed for ICRF-159 under the experimental conditions employed might be connected with the observation that the antimetastatic action of this drug on solid tumors is due to its effects on tumor blood vessels.     

The acute effects of 3-nitropropionic acid on the behavior and spontaneous cortical electrical activity of rats

In this study, the acute effect of 3-nitropropionic acid was investigated on open field and startle behavior of rats, and on their cortical electrical activity. Spontaneous locomotor activity, acoustic startle response, and pre-pulse inhibition of acoustic startle were measured in male Wistar rats (10 weeks old, 180-200 g body weight) after a single dose of 10 or 20 mg/kg i.p. 3-nitropropionic acid. After the behavioral tests, the rats were anaesthetized, and spontaneous cortical electrical activity was recorded. The vertical, horizontal and local open field performance showed dose-dependent deterioration in the rats treated with 3-nitropropionic acid. The number of "noise-positive" startle responses showed non-significant changes, but the inhibition by pre-pulse was significantly reduced in the high dose animals. High dose also increased the proportion of low-frequencies in the cortical activity. 3-nitropropionic acid, known primarily to act in repeated doses (e.g., in animal models of Huntington's disease) had also some clear-cut acute effects on behavioral and electrophysiological parameters of the treated rats.     

Chemotherapy-evoked painful peripheral neuropathy: analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit

Chemotherapeutics in the taxane and vinca-alkaloid classes sometimes produce a painful peripheral neuropathy for which there is no validated treatment. Experiments with rat models of paclitaxel- and vincristine-evoked pain suggest that these conditions may not respond to all of the analgesics that have efficacy in other models of painful peripheral neuropathy. We tested gabapentin as a potential analgesic for paclitaxel- and vincristine-evoked pain. We used a repeated dosing paradigm because there are precedents showing that repeated drug exposure may be necessary to demonstrate analgesia in neuropathic pain models. Gabapentin is believed to work via binding to voltage-gated calcium channels that contain the alpha-2-delta type-1 (alpha(2)delta-1) subunit, and the expression of this subunit is known to be increased in some painful peripheral neuropathy models. Thus we also examined whether the paclitaxel-evoked pain syndrome was accompanied by an alpha(2)delta-1 increase, and whether gabapentin had any effect on subunit expression. We found that the paclitaxel- and vincristine-evoked mechano-allodynia and mechano-hyperalgesia were significantly reduced by gabapentin, but only with repeated dosing. Paclitaxel-evoked painful peripheral neuropathy was associated with an increased expression of the alpha(2)delta-1 subunit in the spinal dorsal horn, but not in the dorsal root ganglia. The spinal cord increase was normalized by repeated gabapentin injections. Together, these findings suggest that repeated dosing with gabapentin may be beneficial in patients with chemotherapy-evoked painful peripheral neuropathy and that gabapentin's mechanisms of action may include normalization of the nerve injury-evoked increase in calcium channel alpha(2)delta-1 subunit expression.     

Enhanced prepulse inhibition of startle using salient prepulses in rats.

Prepulse inhibition (PPI) of the startle reflex occurs when a non-startling stimulus is presented shortly prior to the startling stimulus. PPI is an operational measure for sensorimotor gating. PPI in humans is enhanced by attention, but there is no evidence yet for attentional modulation of PPI in animals. We here combined PPI and conditioned inhibition paradigms in order to investigate attentional modulation of PPI in rats. PPI was assessed before and after training for conditioned inhibition of fear with the conditioned stimulus (auditory CS) and conditioned inhibitor (visual CI) as prepulses. The CI significantly enhanced PPI after training, whereas presentation of the CS had no effect on PPI. These data suggest attentional modulation of PPI in rats by biologically salient prestimuli. This new paradigm may be useful for examining attentional modulation of PPI in animals and to compare attentional modulation in humans and animals.     

Uremic polyneuropathy: different effects of hemodialysis and continuous ambulatory peritoneal dialysis

Registrations of clinical signs of neuropathy, quantified according to a fixed protocol, and determinations of vibratory perception thresholds and nerve conduction velocities (NCV) were performed in 22 patients treated with hemodialysis (HD) and in 21 patients treated with continuous ambulatory peritoneal dialysis (CAPD). Measurements were made at the start of dialysis and during a follow-up period of about 30 months. Motor NCV decreased in both groups; vibratory thresholds increased markedly in the CAPD patients, but not in the HD patients; and the clinical signs worsened in the HD patients, but not in the CAPD patients. The difference in outcome of the clinical signs during HD and CAPD was not of such a magnitude that one of these dialysis forms should be preferred before the other as regards neuropathy. We conclude that peripheral neuropathy may deteriorate during both HD and CAPD, but in significantly different ways, indicating that several pathogenetic mechanisms are probably involved in uremic neuropathy.     

Lipodystrophy and adrenal insufficiency: potential mediators of peripheral neuropathy in HIV infection?

The mechanisms behind certain co-morbid conditions associated with chronic HIV disease still remain elusive. HIV-associated peripheral neuropathy is one among those rarely studied manifestations in HIV-1 infection. Numerous underlying factors associated with peripheral neuropathy have been described in HIV disease. Herein, we hypothesized certain heretofore undescribed potential mechanisms that lead to HIV associated neuropathy. Being a multifactoral manifestation, HIV-associated neuropathy is presumed to have an association with physiological factors namely, adrenal inadequacy/steroid resistance and lipodystrophy-induced cushion-effect loss in peripheral nerves. Therefore, management of the adrenals with steroids at the time-point of high inflammatory burden thereby preventing lipodystrophy by selecting the optimum treatment regimen could markedly alleviate the severity of HIV-associated neuropathic manifestations.     

Demyelination,strokes, and eculizumab: Lessons from the congenital CD59 gene mutations

Neurological symptoms of patients with p.Cys89Tyr mutation in the CD59 gene include recurrent peripheral neuropathy resembling Guillain-Barré syndrome, characterized by sensory-motor demyelinating neuropathy with secondary axonal damage and moderate enhancement of the nerve roots on spine MRI, together with recurrent strokes and retinal involvement. Three additional mutations in CD59, leading to loss of function, have been described, and overall, 12/12 (100%) of patients with any mutation presented with neurological symptoms; 11/12 (92%) patients presented with recurrent peripheral neuropathy, 6/12 (50%) with recurrent strokes, and 1/12 (8%) with retinal involvement. We review the possible thrombophilic profile associated with the mutations. In these patients, excessive intravascular hemolysis saturates scavenger mechanisms resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide to form nitrate and methemoglobin, leading to arterial thrombosis. CD59 loss of function is also one of the major thrombophilic mechanisms in patients with paroxysmal nocturnal hemoglobinuria. We then describe the relationship with demyelination. The lack of CD59 allows uncontrolled complement amplification following low-level spontaneous-, viral-, or post viral-induced complement activation, resulting in severe demyelination in the peripheral nervous system. It is interesting, and certainly encouraging, that after 3 years, following 4 patients with Cys89Tyr mutations who are treated with eculizumab, no strokes occurred and non-permanent neurological insults underwent resolution without any new neurological exacerbations.     

Induction of mutant lymphocytes in cyclophosphamide- and chlorambucil-treated patients

Monitoring patients treated with single antineoplastic agents is aiding our understanding of what hazard these drugs pose in vivo. In this study, the frequency of mutant 6-thioguanine-resistant (TG(R)) peripheral blood lymphocytes was monitored before treatment and for < or =35 weeks after treatment of patients with cyclophosphamide (CP) or chlorambucil (CAB). The mean mutant frequency before treatment for six multiple sclerosis patients treated with high-dose CP was 2.53 x 10(-5) and increased after treatment to 4.61 x 10(-5) (P = 0.08, paired t-test). Using each patient as their own control, there were significant increases (each at P < 0.04) detectable within 2-4 weeks in four of the multiple sclerosis patients treated with CP. There was no increase in an untreated control monitored over the same period. In a patient receiving five sequential CP treatments at 1 month intervals, there were cumulative increases in the frequency of mutant cells. The mutant frequency increased from 0.31 x 10(-5) before treatment to 3.64 x 10(-5) after the final treatment and had decreased to 0.53 x 10(-5) at 35 weeks after treatment. In one of two CAB-treated patients with indolent non-Hodgkin's lymphoma, there was a significant increase in mutant frequency (P < 0.03) after treatment. Freshly isolated peripheral blood lymphocytes treated with 4-hydroperoxy-CP in vitro demonstrate a dose-dependent increase in mutant frequency. The increment in mutant frequency observed in vivo is of the order expected from the in vitro experiments. Although this study demonstrates that single or multiple doses of a single antineoplastic agent are mutagenic in vivo for some patients, further studies are needed to determine the extent and mechanism of the inter-individual variations in mutagenic response.     

Inhibition of Prepotent Responding and Attentional Flexibility in Treated Phenylketonuria

Inhibition of prepotent responding and attentional flexibility were assessed in 58 early and continuously treated phenylketonuria (PKU) patients and 69 controls, age 7 to 14 years. A computerized task was used requiring participants to process consecutive stimuli according to various attentional sets. Analysis of error rate suggested poorer inhibition of prepotent responding in PKU patients compared with controls. No influence of concurrent plasma phenylalanine (phe) was shown, neither in the younger (age < 11 years) nor in the older participants (age sup3; 11 years). Analysis of error rate provided strong evidence for poorer attentional flexibility in PKU patients compared with controls. The difference between attentional flexibility in controls and PKU patients could mainly be attributed to younger PKU patients, with concurrent phe levels higher than 360μmol/L.Younger PKU patients with phe levels below 360 μmol/L performed at the same level as age-matched controls.

Performance of PKU patients was strongly associated with phe levels in age periods during the first 10 years of life, which are characterized by a strong development of executive functioning (ages 2-7 and age 9). High phe levels during these age periods could delay development of inhibitory control and attentional flexibility.

With regard to treatment, analyses with lifetime and concurrent phe levels support strict dietary control throughout the first decade of life, after which the phe-restricted diet can be relaxed. However, based on the evidence that development of specific executive functions continues until approximately age 12, it is recommended to maintain phe levels below 360 μmol/L throughout early adolescence.     

Inhibition of prepotent responding and attentional flexibility in treated phenylketonuria

Inhibition of prepotent responding and attentional flexibility were assessed in 58 early and continuously treated phenylketonuria (PKU) patients and 69 controls, age 7 to 14 years. A computerized task was used requiring participants to process consecutive stimuli according to various attentional sets. Analysis of error rate suggested poorer inhibition of prepotent responding in PKU patients compared with controls. No influence of concurrent plasma phenylalanine (phe) was shown, neither in the younger (age < 11 years) nor in the older participants (age > or = 11 years). Analysis of error rate provided strong evidence for poorer attentional flexibility in PKU patients compared with controls. The difference between attentional flexibility in controls and PKU patients could mainly be attributed to younger PKU patients, with concurrent phe levels higher than 360 micromol/L. Younger PKU patients with phe levels below 360 micromol/L performed at the same level as age-matched controls. Performance of PKU patients was strongly associated with phe levels in age periods during the first 10 years of life, which are characterized by a strong development of executive functioning (ages 2-7 and age 9). High phe levels during these age periods could delay development of inhibitory control and attentional flexibility. With regard to treatment, analyses with lifetime and concurrent phe levels support strict dietary control throughout the first decade of life, after which the phe-restricted diet can be relaxed. However, based on the evidence that development of specific executive functions continues until approximately age 12, it is recommended to maintain phe levels below 360 micromol/L throughout early adolescence.     

The effect of salt-water bath in the management of treatment-related peripheral neuropathy in cancer patients receiving taxane and platinum-based treatment

ObjectivesIn a clinical setting, patients have been observed to complain of discomfort and to discontinue treatment because of chemotherapy-induced peripheral neuropathy. This experimental study was conducted to determine the effect of a salt-water bath in the management of chemotherapy-induced peripheral neuropathy.MethodOne hundred and three patients who received taxane and platinum-based chemotherapy due to cancer and developed peripheral neuropathy associated with the treatment between December 2018 and June 2020 were included in the study. The patients were assigned to the control and experimental groups (1-warm salt-water and 2-cold salt-water) following the randomization checklist. While control groups did not receive any interventions, the patients in the salt-water group were asked to apply warm (41 °C) or cold-water (23–26 °C) baths to their hands/feet for 30 min every other day for 14 days. The data were collected at the beginning of the study and at the end of its first and second weeks using the Patient Information Form and National Cancer Institute (NCI)-CTCAE v5.0 toxicity criteria as well as the EORTC QLQ-C30 and EORTC QLQ-CIPN20 quality of life scales.ResultsThe patients had a mean age of 55.6 ± 10.3, and most of them were treated following a breast cancer diagnosis. At the beginning of the study, Grade 3 peripheral neuropathy severity and quality of life scores of the cold/warm salt-water and control groups were similar. Due to repeated follow-ups, it was determined that the peripheral neuropathy severity decreased and the quality of life scores increased statistically significantly in the patients in the cold salt-water bath group compared to the control group.ConclusionThis study's results suggest that a cold salt-water bath can be an effective approach in managing the development of peripheral neuropathy due to taxane and platinum-based treatment.     

Simply stated: feelings, whoa-oh-oh feelings...

Over 30 percent of persons with HIV/AIDS report having the tingling sensations in the outer extremities associated with peripheral neuropathy. Peripheral neuropathy cannot be prevented but it can be treated. Lists are presented of the types of drugs that can cause peripheral neuropathy and the therapies for its treatment. A list is provided of non-drug methods for relieving some of the pain associated with peripheral neuropathy.     

血浆同型半胱氨酸水平与糖耐量减低患者周围神经病变的相关性研究

目的 探讨血浆同型半胱氨酸水平与糖耐量减低(IGT)周围神经病变的相关性.方法 根据常规神经传导检测结果,选取IGT患者80例,其中40例伴有周围神经病变(IGT-PN),40例无周围神经病变(IGT-NPN),同时选取40名健康者作为对照.采用酶速率法分别对3组受试者进行血浆同型半胱氨酸水平检测,通过多伦多临床评分系统(TCSS)对神经病变的严重程度进行评分与分级.结果 研究对象中,IGT组血浆同型半胱氨酸水平均高于健康对照组.IGT-PN组血浆同型半胱氨酸水平为(14.2±2.7) μmol/L,显著高于IGT-NPN组的(12.3±2.6) μmol/L,其差异具有统计学意义(P＜0.05).回归分析表明血浆同型半胱氨酸水平对IGT合并周围神经病变具有独立作用.血浆同型半胱氨酸水平与TCSS评分呈显著正相关.结论 血浆同型半胱氨酸可能具有促进IGT患者伴发周围神经病变的作用,其水平与IGT患者周围神经病变的严重程度相关.