Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation

Oxaliplatin is a platinum-based anticancer drug used to treat metastatic colorectal, breast, and lung cancers. While oxaliplatin kills cancer cells effectively, it exhibits several side effects of varying severity. Neuropathic pain is commonly experienced during treatment with oxaliplatin. Patients describe symptoms of paresthesias or dysesthesias that are triggered by cold (acute neuropathy), or as abnormal sensory or motor function (chronic neuropathy). In particular, we found that aluminum levels were relatively high in some cancer patients suffering from neuropathic pain based on clinical observations. Based on these findings, we hypothesized that aluminum accumulation in the dorsal root ganglion (DRG) in the course of oxaliplatin treatment exacerbates neuropathic pain. In mice injected with oxaliplatin (three cycles of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest), we detected cold allodynia using the acetone test, but not heat hyperalgesia using a hot plate. However, co-treatment with aluminum chloride (AlCl_3∙6H₂O; 7 mg/kg i.p. for 14 days: equivalent 0.78 mg/kg of elemental Al) and oxaliplatin (1 cycle of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest) synergistically induced cold allodynia as well as increased TRPAl mRNA and protein expression. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis showed a significant increase in aluminum concentrations in the DRG of mice treated with aluminum chloride and oxaliplatin compared to aluminum chloride alone. Similarly, in a mouse induced-tumor model, aluminum concentrations were increased in DRG tissue and tumor cells after oxaliplatin treatment. Taken together, these findings suggest that aluminum accumulation in the DRG may exacerbate neuropathic pain in oxaliplatin-treated mice.     

Effect of oral aluminum and aluminum citrate on blood level and short-term tissue distribution of aluminum in the rat

Aluminum (Al) absorption seems to be very low, but many factors can enhance it in animals and humans. In the present study, we investigated the acute effect of Na citrate on Al absorption by monitoring Al levels in blood and several tissues. For this purpose, 18 Wistar male rats were divided into 3 groups: control, Al, and Al + Na citrate. After a 14-h fasting period, animals were dosed orally with deionized water, or 2 mmol Al chloride, or 2 mmol Al chloride plus 2 mmol Na citrate. Blood samples were taken before and 1, 2, 4, and 6 h after the gavage. Al concentrations in blood, liver, tibia, kidney, and intestinal wall were determined by ICP-OES. In the Al and Al + citrate groups, Al blood concentrations peaked at 1 h and 2 h with higher levels in the Al + citrate group. Al gavage resulted in an increase in Al level in intestinal wall, but not in the other investigated tissues. Simultaneous gavage of citrate with Al significantly increased its tissue levels in tibia, kidney, and in intestinal wall. Our data show clearly that Al as chloride can be absorbed, but not well retained by the organism tissues. Furthermore, the model used in the present study is appropriate for acute studies to investigate the effect of various compounds on Al absorption in the rat.     

Effects of acute and chronic coingestion of AlCl3 with citrate or polyphenolic acids on tissue retention and distribution of aluminum in rats

Aluminum (Al) is toxic to certain biological systems and has been implicated as a neurotoxic agent in the pathogenesis of Alzheimer’s disease. Intestinal absorption of Al is very low (0.1%), but many organic dietary components are potential chelators of Al and may enhance its absorption and tissue distribution. We examined the effects of acute and chronic coingestion of AlCl₃ with different polyphenolic acids on Al retention and compared to citrate in rats. In experiment 1, animals fasted for 14 h were dosed orally with demineralized water, Al chloride, Al chloride plus sodium citrate, or Al chloride plus a polyphenol acid. Blood samples were taken before and 2 h after the gavage and animals were killed 6 h later. In experiment 2, the rats were adapted on a purified diet for 1 wk and received the following for 4 wk in their experimental diets: AlCl₃, except group 1, plus citrate or a polyphenol acid, except groups 1 and 2. Animals were killed and blood and tissues were sampled. In experiment 1, citrate highly enhanced Al absorption and its tissue retention. Gallic and chlorogenic acids significantly increased tibia and kidney Al levels compared to the Al group. In experiment 2, Al levels in the urine were significantly increased in all the Al groups compared to the control group. Significantly higher Al levels in the tibia, kidney, and brain were observed in the citrate group and a significant increase in brain Al level was also noted in the chlorogenic acid group compared to AlCl₃ group. This may suggest a possible relation structure-activity of polyphenol acids. However, further studies are necessary to better understand the influence of polyphenol acids on Al metabolism, in particular that of chlorogenic acid.     

Fate of aluminium and nickel in soil. Evaluation through lysimeters under laboratory conditions

ABSTRACT

Nanomaterials (Nms) applications and environmental deposition are continuously increasing. Aluminum (Al) and nickel (Ni) fate in soil, both from gamma alumina-based Nms and as chloride salts were evaluted through lysimeters. After 85 days of treatment, which included irrigation and collection of eluates, the soil of each lysimeter was divided into four sections. The metal concentration was analyzed in eluates, soil samples, and extracts. Al and iron (Fe) present in soil eluted from Control lysimeter. Al from Nms suspension treatment was quantified in the eluates since 30 days on. Ni eluted upon solid salt deposition on top of one device. These results indicate that Al and Ni applied under certain conditions on soil, could leach and reach groundwater. The total concentration and bioavailability (extractable metals) of Al and Fe in soils showed similar patterns. Ni was retained only in the soil of devices treated with chloride salts. Bioavailability % results were of concern for Ni under certain conditions of treatment: 15.57% and 11.08% in two chloride salt-treated lysimeters versus 0.55% and 0.47% of those in control and treated with Nms lysimeters. Conducting studies with different kinds of soil and longer treatment periods should be useful to understand Nms-metals fate in the environment. The results presented here constitute important evidences both for significant metal release from Nms and elution and for considerable Ni bioavailability, after deposition on soil in the form of Nms or as a chloride salt, respectively. Then, possible toxic effects could occur through exposure of aquatic and terrestrial organisms.     

Effects of aluminum chloride on normal and uremic adult male rats

Normal and uremic adult male rats were given a daily ip injection of 20 mg Al (Al chloride)/kg for 14 d. The results indicate that Al induces a significant decrease in food ingestion, weight gain, and total protein concentration in the plasma. Compared with control animals, very high increases in Al levels were found in plasma and hepatic homogenates (about 36 and 19 times, respectively). In the brain homogenates, the Al increases were lower (about 23%). The brain cholineacetyltransferase activity was reduced: 10.6 and 14.9% in normal and uremic rats, respectively. The nephrectomy and the food restriction did not affect the total protein concentrations in plasma and the cerebral cholineacetyltransferase activity. Both were only found to be reduced in the rats treated by Al chloride.     

Accumulation of aluminum in rat brain: does it lead to behavioral and electrophysiological changes?

The present study was undertaken to examine possible aluminum (Al) accumulation in the brain of rats and to investigate whether subchronic exposure to the metal leads to behavioral and neurophysiological changes in both treated and control groups. Each of the groups consisted of 10 animals. Aluminum chloride (AlCl₃) at a low (50 mg/kg/d) or high (200 mg/kg/d) dose was applied to male Wistar rats by gavage for 8 wk. Al-free water by gavage was given to the control group throughout the experiment. Behavioral effects were evaluated by open-field (OF) motor activity and by acoustic startle response (ASR). Electrophysiological examination was done by recording spontaneous activity and sensory-evoked potentials from the visual, somatosensory, as well as auditory cortex. The Al content of each whole brain was determined by electrothermal atomic absorption spectrophotometry. Subchronic Al exposure slightly caused some changes in the evoked potentials and electrocorticograms and in the OF and ASR performance, but these results were not statistically significant. The brain Al levels of the control and the low and high dose of Al-exposed groups were measured as 0.717±0.208 μg/g (wet weight), 0.963±0.491 μg/g (wet weight) and 1.816±1.157 μg/g (wet weight), respectively.     

Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition

Synaptic inhibition by GABA(A) and glycine receptors, which are ligand-gated anion channels, depends on the electrochemical potential for chloride. Several potassium-chloride cotransporters can lower the intracellular chloride concentration [Cl(-)](i), including the neuronal isoform KCC2. We show that KCC2 knockout mice died immediately after birth due to severe motor deficits that also abolished respiration. Sciatic nerve recordings revealed abnormal spontaneous electrical activity and altered spinal cord responses to peripheral electrical stimuli. In the spinal cord of wild-type animals, the KCC2 protein was found at inhibitory synapses. Patch-clamp measurements of embryonic day 18.5 spinal cord motoneurons demonstrated an excitatory GABA and glycine action in the absence, but not in the presence, of KCC2, revealing a crucial role of KCC2 for synaptic inhibition.     

Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus

Several plasma membrane chloride channels are well characterized, but much less is known about the molecular identity and function of intracellular Cl- channels. ClC-3 is thought to mediate swelling-activated plasma membrane currents, but we now show that this broadly expressed chloride channel is present in endosomal compartments and synaptic vesicles of neurons. While swelling-activated currents are unchanged in mice with disrupted ClC-3, acidification of synaptic vesicles is impaired and there is severe postnatal degeneration of the retina and the hippocampus. Electrophysiological analysis of juvenile hippocampal slices revealed no major functional abnormalities despite slightly increased amplitudes of miniature excitatory postsynaptic currents. Mice almost lacking the hippocampus survive and show several behavioral abnormalities but are still able to acquire motor skills.     

Effects of aluminum and deferoxamine on concentration of essential elements in animals experimentally intoxicated with aluminum]

To assess the effect of aluminium intoxication in tissues of experimental animals on Ca, Mg, Zn, Cu, and Fe concentration, aluminium nitrate was administered intraperitoneally to mice at a daily dose of 0.27 mMol/kg for 5 weeks. Concentration of Al, Ca, Mg, Zn, Cu, and Fe were analyzed by atomic absorption spectrometry. The Al content in liver and tibia was significantly higher in treated mice in comparison with control group. In Al loaded tissues the significant increase of all tested essential elements was found. To evaluate the results of DFO treatment on essential elements, mice received 6 times intraperitoneally 3.5 mMol/kg of DFO. This treatment had generally no effect on reduction of Al concentration in tibia and liver, as well as on changes in essential elements concentration.     

Memory Deficit in Mice Administered Aluminum–maltolate Complex

Recently, aluminum (Al) has been identified as one of the environmental factors responsible for cause certain nerve degeneration diseases, particularly, Alzheimer’s disease (AD). However, the relationship between Al and AD is controversial. We previously examined whether Al induced neurotoxin in the brain of mice when aluminum–maltolate complex (ALM) was administered daily for 120 days. Our results revealed that Al accumulated in the brain induced oxidative stress, and the nerve degeneration was detected in the brain of the ALM-treated group. On the basis of these results, we have tried to examine whether the incorporated Al affects memory in mice with regard to an indicator of spatial memory deficits depending on the chemical forms of Al, namely, as an ion (AlCl₃) and in the form of a complex (ALM). We administered saline, AlCl₃, and ALM at a concentration of 40 μmol Al/kg body weight to mice by daily ip injections for 60 days. We assessed spatial memory by a water maze task and determined the Al levels in the brain of the mice by the neutron activation analysis method. Spatial memory deficit as an indicator of the swimming time was related to Al accumulation in the brain of mice; the chemical form of the Al compound was important in order to exhibit the memory deficit in mice; the uptake of Al is higher in mice when it is administered in a complex form than in an ionic form.     

Orally administrated aluminum-maltolate complex enhances oxidative stress in the organs of mice

Recently, aluminum (Al) in drinking water has been proposed to be a risk factor for development of Alzheimer's disease (AD). Because the physiological role of Al in humans is not yet known, we previously examined this role using an experimental animal model. Our results revealed a greater accumulation of Al in the brain, liver, kidney and spleen of mice who received long-term (90 days) administration of an Al complex, aluminum-maltolate (ALM), than in untreated controls. This observation prompted us to examine the degree of injury in the organs of mice in terms of lipid peroxidation evaluated by thiobarbituric acid reactive substances (TBARS) and NOx levels in order to determine the effects of Al accumulation. Six-week-old mice were given drinking water containing AlCl3 or ALM for 120 days. TBARS and NOx levels were found to change depending on the organs and chemical forms of Al. In particular, TBARS and NOx levels in the brain of mice given ALM for 30, 60 and 120 days were significantly increased compared with those of the control group. In addition, nervous degeneration was detected in the brain of the ALM-treated group. These results indicate that the chemical form of Al alters the distribution and oxidative stress in the brain. In addition, we propose a more precise method of determining Al levels in biological systems using neutron activation analysis. When the biological samples are irradiated with a neutron flux, both 27Al and 31P can be counted to 28Al by the reactions, 27Al(n,gamma)28Al and 31P(n,alpha)28Al, respectively. The level of Al in the organs can then be determined by subtraction of the radioactivity due to 28Al originated in 31P from the total radioactivity of the samples.     

Remote ischaemic preconditioning and prevention of cerebral injury

Bilateral carotid artery occlusion of 10 min followed by reperfusion for 24 hr was employed in present study to produce ischaemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Short-term memory was evaluated using elevated plus maze. Inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired short-term memory, motor co-ordination and lateral push response. A preceding episode of mesenteric artery occlusion for 15 min and reperfusion of 15 min (remote mesenteric ischaemic preconditioning) prevented markedly ischaemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of short-term memory, motor coordination and lateral push response. Glibenclamide (5 mg/kg, iv) a KATP channel blocker and caffeine (7 mg/kg, iv) an adenosine receptor blocker attenuated the neuroprotective effect of remote mesenteric ischaemic preconditioning. It may be concluded that neuroprotective effect of remote mesenteric ischaemic preconditioning may be due to activation of adenosine receptors and consequent activation of KATP channels in mice.     

Effect of aluminum on iron-induced lipid peroxidation and protein oxidative modification of mouse brain homogenate

In the present study the authors report on the enhancing effect of aluminum(III) (Al[III]) on iron(II)(Fe[II])-induced lipid peroxidation (LPO) of mice brain homogenate, which occurs in a concentration and time-dependent manner. No evidence of LPO caused by Al alone was found. Both Al(III) and Fe(II) ions induced protein oxidative modifications in mice brain homogenate, in a time and concentrationdependent manner. Aluminum enhances Fe(II)-induced protein oxidative modification at a concentration of 2:1 and 1:1 Al:Fe molar ratios. However, Al suppress Fe(II)-induced protein oxidative modification at a concentration of 0.5:1 Al:Fe molar ratio. Addition of ethylenediaminetetraacetic acid (EDTA) inhibits both LPO and protein oxidative modifications induced by Al(III) and Fe(II) ions. Addition of mannitol and of Superoxide dismutase (SOD) did not show such effects. It is concluded that in mice brain homogenate, Al accelerates Fe(II)-induced LPO. Protein oxidative modifications caused by Fe(II) and/or Al ions are enhanced at high, but suppressed at low concentrations of Al ions. The latter observation suggests a possible biological role of Al as an antioxidant.     

Age‐related deterioration of motor function in male and female 5xFAD mice from 3 to 16 months of age

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to age‐related cognitive and sensori‐motor dysfunction. There is an increased understanding that motor dysfunction contributes to overall AD severity, and a need to ameliorate these impairments. The 5xFAD mouse develops the neuropathology, cognitive and motor impairments observed in AD, and thus may be a valuable animal model to study motor deficits in AD. Therefore, we assessed age‐related changes in motor ability of male and female 5xFAD mice from 3 to 16 months of age, using a battery of behavioral tests. At 9‐10 months, 5xFAD mice showed reduced body weight, reduced rearing in the open‐field and impaired performance on the rotarod compared to wild‐type controls. At 12‐13 months, 5xFAD mice showed reduced locomotor activity on the open‐field, and impaired balance on the balance beam. At 15‐16 months, impairments were also seen in grip strength. Although sex differences were observed at specific ages, the development of motor dysfunction was similar in male and female mice. Given the 5xFAD mouse is commonly on a C57BL/6 × SJL hybrid background, a subset of mice may be homozygous recessive for the Dysf ^im mutant allele, which leads to muscular weakness in SJL mice and may exacerbate motor dysfunction. We found small effects of Dysf ^im on motor function, suggesting that Dysf ^im contributes little to motor dysfunction in 5xFAD mice. We conclude that the 5xFAD mouse may be a useful model to study mechanisms that produce motor dysfunction in AD, and to assess the efficacy of therapeutics on ameliorating motor impairment.     

Pomegranate juice rescues developmental,neurobehavioral and biochemical disorders in aluminum chloride-treated male mice

PurposeAluminum (Al) is a harmful metal to organisms and is capable of entering the human body in multiple ways, such as through drinking, breathing, deodorant use, and vaccination. This study examined the prospective toxicity of Al and the protective attributes of pomegranate juice (PJ) on neurobehavioral and biochemical parameters of male mice.MethodsSix groups of male mice were treated for 35 days with 20 % PJ (group II), 40 % PJ (group III), 400 mg/kg Al (group IV), Al + 20 % PJ (group V), Al + 40 % PJ (group VI) or tap water (control, group I). Behavioral assessments were conducted for learning and memory evaluations at the end of experiment. In addition, the forebrain was isolated for biochemical analysis.ResultsThe exposure of male mice to Al decreased learning and memory retention in the shuttle box, Morris water-maze and T-Maze tests. Biochemical analysis revealed significant depletions in neurotransmitters including DA, 5-HT and AChE and oxidative proteins including GSH, GST, CAT and SOD and increased TBARES levels in Al-treated mice compared to untreated mice. Pomegranate juice provided protection against these effects after Al exposure by ameliorating learning and memory retention and oxidative state in a dose-independent manner.ConclusionOur data demonstrated that Al exposure caused behavioral and biochemical disorders. Pomegranate juice in lower dose has beneficial properties for health and can be used as a source of antioxidants to reduce the toxicity of Al and other substances.     

Effects of thiazole analogs of vitamin B1 on neuromuscular transmission and α-latrotoxin-induced transmitter release in skeletal muscles

Thiazole analogs of vitamin B₁ 3-decyloxycarbonylmethyl-4-methyl-5-(2-hydroxyethyl)thiazole chloride (DMHT) and 3-decyloxycarbonylmethyl-4-methylthiazole chloride (DMT) suppress quantum transmitter release from nerve terminals in the frog skeletal muscle. Intraperitoneal administration of these compounds to mice suppresses behavioral motor activity, diminishes motor coordination, and suppresses the corazol-induced seizures. Application of DMHT reduces the -latrotoxin-induced massive transmitter release from nerve terminals in the frog skeletal muscle and suppresses latrotoxin-induced seizures in mice. In model experiments, DMHT blocks Ca²⁺ entry through the ion channels formed by -latrotoxin in a bilayer lipid membrane. It has been suggested that the effectiveness of DMHT and DMT is determined by the presence of a thiazole cycle in their molecules that, among all endogenous biologically active compounds, is possessed only by vitamin B₁ and its metabolites.Neirofiziologiya/Neurophysiology, Vol. 27, No. 5/6, pp. 368–374, September–December, 1995.     

Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold

K-Cl co-transporters are encoded by four homologous genes and may have roles in transepithelial transport and in the regulation of cell volume and cytoplasmic chloride. KCC3, an isoform mutated in the human Anderman syndrome, is expressed in brain, epithelia and other tissues. To investigate the physiological functions of KCC3, we disrupted its gene in mice. This severely impaired cell volume regulation as assessed in renal tubules and neurons, and moderately raised intraneuronal Cl(-) concentration. Kcc3(-/-) mice showed severe motor abnormalities correlating with a progressive neurodegeneration in the peripheral and CNS. Although no spontaneous seizures were observed, Kcc3(-/-) mice displayed reduced seizure threshold and spike-wave complexes on electrocorticograms. These resembled EEG abnormalities in patients with Anderman syndrome. Kcc3(-/-) mice also displayed arterial hypertension and a slowly progressive deafness. KCC3 was expressed in many, but not all cells of the inner ear K(+) recycling pathway. These cells slowly degenerated, as did sensory hair cells. The present mouse model has revealed important cellular and systemic functions of KCC3 and is highly relevant for Anderman syndrome.     

The effects of Al(III) speciation on the activity of trypsin

The effects of the different forms of Al(III) on the catalytic activity of the serine protease trypsin were studied. Enzyme activity was measured by BAEE assay in the presence of AlCl(3), Al(III):lactic acid 1:3, Al(III):maltol 1:3 or Al(III):nitrilotriacetic acid (NTA) 1:1 at a nominal Al(III) concentration of 0.01 M, and the ligand alone at pH 7.4 at 25 degrees C. Maltol and NTA caused approximately 30% inhibition, while that for the corresponding Al(III) complex was less than half of this. Al(III) in the form of the chloride or in three equivalents of lactic acid did not influence the activity of the enzyme, probably because most of the Al(III) was precipitated as Al(OH)(3). No direct interaction could be detected between the enzyme and the Al(III) complexes, either by ultrafiltration or by CD spectroscopy. These results strongly suggest that there is no direct involvement of Al(III) in the enzymatic reactions of trypsin.     

Migration of Al(OH)3 in the bodies of experimental animals

The aim of this study was to observe aluminium hydroxide distribution in mice given this substance subcutaneously and intraperitoneally in various concentrations (0.03 mg-0.8 mg of Al3+ per dose). Each experimental group consisted of 5-6 mice of which brain, liver and kidney were isolated after 7, 14, 28, and 35 days after injection. Control group was composed of unvaccinated mice. Sera of animals vaccinated subcutaneously with the following doses: 0.2 mg, 0.4 mg and 0.8 mg were also tested. A distinct accumulation of Al3+ in liver after intraperitoneal injection with a tendency of rising after 28 days of observation was seen. The same was observed in kidneys after subcutaneous injection, especially doses of 0.4 mg Al3+ and 0.8 mg Al3+. The aluminium content in sera was high in an early period of observation only, and subsequently its elimination was fast.     

Behavioral effects of the aqueous extract of Guiera senegalensis in mice and rats

Behavioral effects of the aqueous extract of Guiera senegalensis on the central nervous system of mice and rats were investigated. Spontaneous motor activity, pentobarbital sleeping time, amphetamine-stereotyped behavior, exploratory activity and performance on treadmills (rota-rod) were evaluated. The results revealed that the aqueous extract of G. senegalensis reduced spontaneous motor activity in mice, prolonged the duration of pentobarbital sleeping time in rats and attenuated amphetamine-induced stereotype behavior in rats. The extract also decreased exploratory activity in mice and had no observable effects on motor coordination (rota-rod) at the doses tested. The results suggested that the crude aqueous extract of G. senegalensis possesses some biologically active principles that are sedative in nature.