Histological and ultrastructural study of AflatoxinB1 induced neurotoxicity in Sciatic nerve of adult male Albino rats.

Aflatoxins are mycotoxins produced by Aspergillus spp. which is a common contaminant of food items such as corn, spices, rice, nuts, and flour. Aflatoxin contamination of foods is a worldwide problem. Chronic aflatoxin exposure is found to be associated with Sciatic nerve damage. In vivo study was carried out to evaluate the toxic effect of aflatoxin B1 (AFB1) on the Sciatic nerve. Twenty-one adult male rats were included and divided equally into 3 groups (7 rats each): Group I (control group), group II (olive oil group) and group III: (AflatoxinB1 group). The rats received AFB1 (250 µg/kg B.W./day) orally by gastric tube 5 days/week for 4 weeks. Sciatic nerve specimens were prepared, and semi-thin sections were stained with Toluidine blue, examined by light microscope and photographed. Ultrathin sections (50-80 nm) from selected areas of the trimmed blocks were made, examined and photographed by transmission electron microscopy (JEOL-JSM-1011) in King Saud University Electron Microscopy Unit. The findings indicate that the administration of AFB1 to rats' results in degeneration in the sciatic nerve in the form of Wallerian degeneration in the myelin sheath. Macrophages appear to engulf the degenerated myelin and neutrophils.

The mitochondrial Nod-like receptor NLRX1 modifies apoptosis through SARM1.

NLRX1, the mitochondrial NOD-like receptor (NLR), modulates apoptosis in response to both intrinsic and extrinsic cues. Insights into the mechanism of how NLRX1 influences apoptosis remain to be determined. Here, we demonstrate that NLRX1 associates with SARM1, a protein with a toll/interleukin-1 receptor (TIR)-containing domain also found in adaptor proteins downstream of toll-like receptors, such as MyD88. While a direct role of SARM1 in innate immunity is unclear, the protein plays essential roles in Wallerian degeneration (WD), a type of neuronal catabolism occurring following axonal severing or damage. In non-neuronal cells, we found that endogenous SARM1 was equally distributed in the cytosol and the mitochondrial matrix, where association with NLRX1 occurred. In these cells, the apoptotic role of NLRX1 was fully dependent on SARM1, indicating that SARM1 was downstream of NLRX1 in apoptosis regulation. In primary murine neurons, however, Wallerian degeneration induced by vinblastine or NGF deprivation occurred in SARM1- yet NLRX1-independent manner, suggesting that WD requires the cytosolic pool of SARM1 or that NLRX1 levels in neurons are too low to contribute to WD regulation. Together, these results shed new light into the mechanisms through which NLRX1 controls apoptosis and provides evidence of a new link between NLR and TIR-containing proteins.

Elevated intracellular Ca2+ functions downstream of mitodysfunction to induce Wallerian-like degeneration and necroptosis in organophosphorus-induced delayed neuropathy.

Neurotoxic organophosphorus compounds can induce a type of delayed neuropathy in humans and sensitive animals, known as organophosphorus-induced delayed neuropathy (OPIDN). OPIDN is characterized by axonal degeneration akin to Wallerian-like degeneration, which is thought to be caused by increased intra-axonal Ca2+ concentrations. This study was designed to investigate that deregulated cytosolic Ca2+ may function downstream of mitodysfunction in activating Wallerian-like degeneration and necroptosis in OPIDN. Adult hens were administrated a single dosage of 750 mg/kg tri-ortho-cresyl phosphate (TOCP), and then sacrificed at 1 day, 5 day, 10 day and 21 day post-exposure, respectively. Sciatic nerves and spinal cords were examined for pathological changes and proteins expression related to Wallerian-like degeneration and necroptosis. In vitro experiments using differentiated neuro-2a (N2a) cells were conducted to investigate the relationship among mitochondrial dysfunction, Ca2+ influx, axonal degeneration, and necroptosis. The cells were co-administered with the Ca2+-chelator BAPTA-AM, the TRPA1 channel inhibitor HC030031, the RIPK1 inhibitor Necrostatin-1, and the mitochondrial-targeted antioxidant MitoQ along with TOCP. Results demonstrated an increase in cytosolic calcium concentration and key proteins associated with Wallerian degeneration and necroptosis in both in vivo and in vitro models after TOCP exposure. Moreover, co-administration with BATPA-AM or HC030031 significantly attenuated the loss of NMNAT2 and STMN2 in N2a cells, as well as the upregulation of SARM1, RIPK1 and p-MLKL. In contrast, Necrostatin-1 treatment only inhibited the TOCP-induced elevation of p-MLKL. Notably, pharmacological protection of mitochondrial function with MitoQ effectively alleviated the increase in intracellular Ca2+ following TOCP and mitigated axonal degeneration and necroptosis in N2a cells, supporting mitochondrial dysfunction as an upstream event of the intracellular Ca2+ imbalance and neuronal damage in OPIDN. These findings suggest that mitochondrial dysfunction post-TOCP intoxication leads to an elevated intracellular Ca2+ concentration, which plays a pivotal role in the initiation and development of OPIDN through inducing SARM1-mediated axonal degeneration and activating the necroptotic signaling pathway.

Tri-ortho-cresyl phosphate induces axonal degeneration in chicken DRG neurons by the NAD+ pathway.

Wallerian degeneration (WD) is a well-known process by which degenerating axons and myelin are cleared after nerve injury. Although organophosphate-induced delayed neuropathy (OPIDN) is characterized by Wallerian-like degeneration of long axons in human and sensitive animals, the precise pathological mechanism remains unclear. In this study, we cultured embryonic chicken dorsal root ganglia (DRG) neurons, the model of OPIDN in vitro, to investigate the underlying mechanism of axon degeneration induced by tri-ortho-cresyl phosphate (TOCP), an OPIDN inducer. The results showed that TOCP exposure time- and concentration-dependently induced a serious degeneration and fragmentation of the axons from the DRG neurons. A collapse of mitochondrial membrane potential and a dramatic depletion of ATP levels were found in the DRG neurons after TOCP treatment. In addition, nicotinamide nucleotide adenylyl transferase 2 (NMNAT2) expression and nicotinamide adenine dinucleotide (NAD+) level was also found to be decreased in the DRG neurons exposed to TOCP. However, the TOCP-induced Wallerian degeneration in the DRG neurons could be inhibited by ATP supplementation. And exogenous NAD+ or NAD+ processor nicotinamide riboside can rescue TOCP-induced ATP deficiency and prevent TOCP-induced axon degeneration of the DRG neurons. These findings may shed light on the pathophysiological mechanism of TOCP-induced axonal damages, and implicate the potential application of NAD+ to treat OPIDN.

Nrf2 deficiency potentiates methamphetamine-induced dopaminergic axonal damage and gliosis in the striatum.

Oxidative stress that correlates with damage to nigrostriatal dopaminergic neurons and reactive gliosis in the basal ganglia is a hallmark of methamphetamine (METH) toxicity. In this study, we analyzed the protective role of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2), a master regulator of redox homeostasis, in METH-induced neurotoxicity. We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons, shown by an increase in loss of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-containing fibers in striatum. Consistent with these effects, Nrf2 deficiency potentiated glial activation, indicated by increased striatal expression of markers for microglia (Mac-1 and Iba-1) and astroglia (GFAP) one day after METH administration. At the same time, Nrf2 inactivation dramatically potentiated the increase in TNFα mRNA and IL-15 protein expression in GFAP+ cells in the striatum. In sharp contrast to the potentiation of striatal damage, Nrf2 deficiency did not affect METH-induced dopaminergic neuron death or expression of glial markers or proinflammatory molecules in the substantia nigra. This study uncovers a new role for Nrf2 in protection against METH-induced inflammatory and oxidative stress and striatal degeneration.

SARM1-mediated wallerian degeneration: A possible mechanism underlying organophosphorus-induced delayed neuropathy.

Some organophosphorus compounds (OPs) can cause a type of delayed neurotoxicity in human being, which is known as organophosphorus-induced delayed neuropathy (OPIDN). Signs and symptoms of the patients include tingling and sensory loss of the hands and feet, followed by progressive muscle weakness in the lower and upper limbs, and ataxia. Pathologically, OPIDN are characterized by distal sensorimotor axonopathy due to the distal axonal degeneration of nerve tracts located in central and peripheral nervous systems. The morphological pattern of the distal axonopathy is similar to Wallerian degeneration that occurs after nerve injury in vitro. It is generally acknowledged that inhibition and subsequent aging of neuropathy target esterase (NTE) is required for the occurrence of OPIDN. However, the underlying mechanisms through which NTE triggers axonal degeneration in OPIDN is still largely unclear. Recently, sterile alpha and toll/interleukin receptor motif-containing protein 1（SARM1) has been identified as a key player in Wallerian degeneration. In physical and chemical transection of axons, SARM1 was found to promotes axon degeneration by hydrolyzing NAD+. By contrast, SARM1 deficiency could prevent neuron degeneration in response to a wide range of insults. Furthermore, SARM1 can also translocate to mitochondria and cause mitochondrial damage, thus triggering axon degeneration and neuron death. These findings suggested the existence of a pathway in axonal degeneration that might be targeted therapeutically. Here, we hypothesize that SARM1 activation after NTE inhibition and aging might be an etiological factor in OPIDN that regulates Wallerian-like degeneration. Analysing SARM1 mediated NAD degeneration pathway and its upstream activators in OPIDN could contribute to the development of novel therapies to treat OPIDN.

Distinct muscarinic acetylcholine receptor subtypes contribute to stability and growth, but not compensatory plasticity, of neuromuscular synapses.

Muscarinic acetylcholine receptors (mAChRs) modulate synaptic function, but whether they influence synaptic structure remains unknown. At neuromuscular junctions (NMJs), mAChRs have been implicated in compensatory sprouting of axon terminals in paralyzed or denervated muscles. Here we used pharmacological and genetic inhibition and localization studies of mAChR subtypes at mouse NMJs to demonstrate their roles in synaptic stability and growth but not in compensatory sprouting. M(2) mAChRs were present solely in motor neurons, whereas M(1), M(3), and M(5) mAChRs were associated with Schwann cells and/or muscle fibers. Blockade of all five mAChR subtypes with atropine evoked pronounced effects, including terminal sprouting, terminal withdrawal, and muscle fiber atrophy. In contrast, methoctramine, an M(2/4)-preferring antagonist, induced terminal sprouting and terminal withdrawal, but no muscle fiber atrophy. Consistent with this observation, M(2)(-/-) but no other mAChR mutant mice exhibited spontaneous sprouting accompanied by extensive loss of parental terminal arbors. Terminal sprouting, however, seemed not to be the causative defect because partial loss of terminal branches was common even in the M(2)(-/-) NMJs without sprouting. Moreover, compensatory sprouting after paralysis or partial denervation was normal in mice deficient in M(2) or other mAChR subtypes. We also found that many NMJs of M(5)(-/-) mice were exceptionally small and reduced in proportion to the size of parental muscle fibers. These findings show that axon terminals are unstable without M(2) and that muscle fiber growth is defective without M(5). Subtype-specific muscarinic signaling provides a novel means for coordinating activity-dependent development and maintenance of the tripartite synapse.

Tau hyperphosphorylation and axonal damage induced by N,N-diethyldithiocarbamate (DEDTC) treatment along late postnatal development is followed by a rescue during adulthood.

Axonal degeneration has been described as the pathological hallmark of peripheral neuropathies induced by DEDTC. In addition, axonal damage has also been observed in the brain of mice treated daily with DEDTC along postnatal development, though with this experimental model there was observed to be axonal recovery after treatment, during the adulthood. To focus on this axonal dynamic activity, damage-recovery, a key axonal protein, the microtubule associated protein tau, was analyzed in this DEDTC model. Tau is a phosphoprotein and its dynamic site-specific phosphorylation is essential for its proper function; in fact, high levels are correlated with cell dysfunction. Furthermore, the levels of tau phosphorylation are associated with dynamic microtubules during periods of high plasticity. Thus, phosphorylated tau at two sites of phosphorylation, Ser(199) and Ser(396), were evaluated during the second week of postnatal development and throughout adulthood. The results obtained by Western blot made it evident that the levels of p-tau Ser(199) and p-tau Ser(396) were higher in treated mice than in controls. Interestingly, by immunohistochemistry there was shown to be an increase in p-tau-immunolabeling in neuronal soma together with axonal tract alterations in treated animals with respect to controls, and the analyses of GSK3 beta and cdk5 revealed an increase in its activity in DEDTC-treated animals. Nevertheless, in the adult a general decline in p-tau was observed together with a rescue of axonal tract. All these data support the idea that the axonal damage induced by DEDTC treatment along postnatal development is followed by an axonal rescue during adulthood.

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study.

BACKGROUND: Excitotoxicity is involved in the pathogenesis of a number neurodegenerative diseases, and axonopathy is an early feature in several of these disorders. In models of excitotoxicity-associated neurological disease, an excitotoxin delivered to the central nervous system (CNS), could trigger neuronal death not only in the somatodendritic region, but also in the axonal region, via oligodendrocyte N-methyl-D-aspartate (NMDA) receptors. The retina and optic nerve, as approachable regions of the brain, provide a unique anatomical substrate to investigate the "downstream" effect of isolated excitotoxic perikaryal injury on central nervous system (CNS) axons, potentially providing information about the pathogenesis of the axonopathy in clinical neurological disorders.Herein, we provide ultrastructural information about the retinal ganglion cell (RGC) somata and their axons, both unmyelinated and myelinated, after NMDA-induced retinal injury. Male Sprague-Dawley rats were killed at 0 h, 24 h, 72 h and 7 days after injecting 20 nM NMDA into the vitreous chamber of the left eye (n = 8 in each group). Saline-injected right eyes served as controls. After perfusion fixation, dissection, resin-embedding and staining, ultrathin sections of eyes and proximal (intraorbital) and distal (intracranial) optic nerve segments were evaluated by transmission electron tomography (TEM). RESULTS: TEM demonstrated features of necrosis in RGCs: mitochondrial and endoplasmic reticulum swelling, disintegration of polyribosomes, rupture of membranous organelle and formation of myelin bodies. Ultrastructural damage in the optic nerve mimicked the changes of Wallerian degeneration; early nodal/paranodal disturbances were followed by the appearance of three major morphological variants: dark degeneration, watery degeneration and demyelination. CONCLUSION: NMDA-induced excitotoxic retinal injury causes mainly necrotic RGC somal death with Wallerian-like degeneration of the optic nerve. Since axonal degeneration associated with perikaryal excitotoxic injury is an active, regulated process, it may be amenable to therapeutic intervention.

Ropivacaine-induced peripheral nerve injection injury in the rodent model.

BACKGROUND: Intraneural administration of local anesthetics has been associated with nerve damage. We undertook the present study to investigate histological changes induced by ropivacaine injection into rat sciatic nerve. METHODS: Fifty-four adult male Lewis rats were randomly distributed into 9 groups, 6 animals per group. Fifty microliters of normal saline, 10% phenol, or 0.75% ropivacaine were administered by intrafascicular injection, extrafascicular injection, or extraneural (topical) placement. At 2 weeks, animals were killed and the sciatic nerve at the injection site was evaluated with light microscopy, quantitative histomorphometry, and electron microscopy. RESULTS: On cross-sectional evaluation, extrafascicular ropivacaine injection and extraneural placement of ropivacaine were both associated with damage to the perineurium, with focal demyelination surrounded by edematous endoneurium. Intrafascicular injection of ropivacaine resulted in a wedge-shaped region of demyelination and focal axonal loss with some regeneration, bordered by a region of normally myelinated axons in a background of edematous endoneurium. Extrafascicular injection resulted in more significant damage than extraneural placement of ropivacaine, but less than intrafascicular injection as shown with quantitative histomorphometry. Quantitatively, ropivacaine-injured specimens had significantly lower nerve density than saline-injured specimens. Wallerian degeneration and perineural edema were also demonstrated qualitatively with electron microscopy. CONCLUSIONS: This study demonstrates that, in the rat model, ropivacaine is associated with marked histological abnormality, including edema of the perineurium and axonal destruction with wallerian degeneration, when injected into or extraneurally placed onto a nerve. Extrafascicular injection and extraneural placement were associated with similar, although milder, histological damage than intrafascicular injection. Further work is needed to investigate the functional implications, if any, of the histological abnormalities observed in this study.

Estrogen reduces BDNF level, but maintains dopaminergic cell density in the striatum of MPTP mouse model.

Degeneration of dopaminergic (DA) axons in the striatum triggers upregulation of striatal trophic activity and striatal DA neuronal number in animal models of Parkinson's disease (PD). The present study investigated the effects of 17beta-estradiol (E2) on brain-derived neurotrophic factor (BDNF) expression and the density of DA neurons in the striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model in correlation with nigrostriatal DA innervation. Adult male C57Bl/6 mice were treated with E2 or vehicle for 11 days. Following 5 days of E2 or vehicle pretreatment, animals were injected with MPTP on day 6. On day 11, all mice were sacrificed, and the striatum were collected and processed for tyrosine hydroxylase (TH) and BDNF immunohistochemistry. Striatal TH-immunoreactive (IR) neurons were counted. Extent of DA innervation and BDNF expression in the striatum were assessed by measuring optical density of TH and BDNF immunoreactivity, respectively. Pretreatment with E2 partially prevented DA denervation and decreased striatal BDNF upregulation triggered by MPTP, but maintained the density of striatal TH-IR neurons to that observed in MPTP group. These findings suggest that estrogen protection of nigrostriatal DA axons against MPTP as well as preservation of the striatal TH-IR cell density in MPTP/E2 mice may be not mediated by BDNF.

Cisplatin induced neurotoxicity is mediated by Sarm1 and calpain activation.

Cisplatin is a commonly used chemotherapy agent with significant dose-limiting neurotoxicity resulting in peripheral neuropathy. Although it is postulated that formation of DNA-platinum adducts is responsible for both its cytotoxicity in cancer cells and side effects in neurons, downstream mechanisms that lead to distal axonal degeneration are unknown. Here we show that activation of calpains is required for both neurotoxicity and formation of DNA-platinum adduct formation in neurons but not in cancer cells. Furthermore, we show that neurotoxicity of cisplatin requires activation of Sarm1, a key regulator of Wallerian degeneration, as mice lacking the Sarm1 gene do not develop peripheral neuropathy as evaluated by both behavioral or pathological measures. These findings indicate that Sarm1 and/or specific calpain inhibitors could be developed to prevent cisplatin induced peripheral neuropathy.

Demyelination of the hippocampus is prominent in the cuprizone model.

In multiple sclerosis demyelination not only affects the white matter, but also the grey matter of the brain. We have previously reported that in the murine cuprizone model for demyelination lesions occur in addition to the corpus callosum also in the neocortex and hippocampus. In the current study, we provide a detailed characterization of hippocampal demyelination in the cuprizone model. Male C57BL/6 mice were challenged with 0.2% cuprizone for 6 weeks. Defined structures within the hippocampus were investigated at week 0 (control), 3, 4, 4.5, 5, 5.5, and 6. Demyelination affected all hippocampal structures analyzed and was complete after 6 weeks of cuprizone treatment. Between the distinct hippocampal structures the temporal pattern of demyelination varied considerably. Furthermore, infiltration of activated microglia as well as astrogliosis was detected. In summary, cuprizone feeding provides a useful model for studying demyelination processes in the mouse hippocampus.

Na(+)/H(+) exchanger inhibition modifies dopamine neurotransmission during normal and metabolic stress conditions.

Na(+)/H(+) exchanger (NHE) proteins are involved in intracellular pH and volume regulation and may indirectly influence neurotransmission. The abundant NHE isoform 1 (NHE1) has also been linked to brain cell damage during metabolic stress. It is not known, however, whether NHE1 or other NHE isoforms play a role in striatal dopamine (DA) neurotransmission under normal or metabolic stress conditions. Our study tested the hypothesis that NHE inhibition with cariporide mesilate (HOE-642) modifies striatal DA overflow and DAergic terminal damage in mice caused by the mitochondrial inhibitor malonate. We also explored the expression of NHE1-5 in the striatum and substantia nigra. Reverse microdialysis of HOE-642 elicited a transient elevation followed by a reduction in DA overflow accompanied by a decline in striatal DA content. HOE-642 pre-treatment diminished the malonate-induced DA overflow without reducing the intensity of the metabolic stress or subsequent DAergic axonal damage. Although NHE isoforms 1-5 are expressed in the striatum and midbrain, NHE1 protein was not co-located on nigrostriatal DAergic neurons. The absence of NHE1 co-location on DAergic neurons suggests that the effects of HOE-642 on striatal DA overflow are either mediated via NHE1 located on other cell types or that HOE-642 is acting through multiple NHE isoforms.

Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats.

We examined the potential protective effect of BDNF against beta-amyloid-induced neurotoxicity in vitro and in vivo in rats. In neuronal cultures, BDNF had specific and dose-response protective effects on neuronal toxicity induced by Abeta(1-42) and Abeta(25-35). It completely reversed the toxic action induced by Abeta(1-42) and partially that induced by Abeta(25-35). These effects involved TrkB receptor activation since they were inhibited by K252a. Catalytic BDNF receptors (TrkB.FL) were localized in vitro in cortical neurons (mRNA and protein). In in vivo experiments, Abeta(25-35) was administered into the indusium griseum or the third ventricle and several parameters were measured 7 days later to evaluate potential Abeta(25-35)/BDNF interactions, i.e. local measurement of BDNF release, number of hippocampal hilar cells expressing SRIH mRNA and assessment of the corpus callosum damage (morphological examination, pyknotic nuclei counting and axon labeling with anti-MBP antibody). We conclude that BDNF possesses neuroprotective properties against toxic effects of Abeta peptides.

Differential changes in axonal conduction following CNS demyelination in two mouse models.

Transgenic and disease model mice have been used to investigate the molecular mechanisms of demyelinating diseases. However, less attention has been given to elucidating changes in nerve conduction in these mice. We established an experimental system to measure the response latency of cortical neurons and examined changes in nerve conduction in cuprizone-induced demyelinating mice and in myelin basic protein-deficient shiverer mice. Stimulating and recording electrodes were placed in the right and left sensori-motor cortices, respectively. Electrical stimulation of the right cortex evoked antidromic responses in left cortical neurons with a latency of 9.38 +/- 0.31 ms (n = 107; mean +/- SEM). While response latency was longer in mice at 7 days and 4 weeks of cuprizone treatment (12.35 +/- 0.35 ms, n = 102; 11.72 +/- 0.29 ms, n = 103, respectively), response latency at 7 days and 4 weeks after removal of cuprizone was partially restored (10.72 +/- 0.45 ms, n = 106; 10.27 +/- 0.34 ms, n = 107, respectively). Likewise, electron microscopy showed cuprizone-induced demyelination in the corpus callosum and nearly complete remyelination after cuprizone removal. We also examined whether the myelin abnormalities in shiverer mice affected their response latencies. But there were no significant differences in response latencies in shiverer (9.83 +/- 0.24 ms, n = 103) and wild-type (9.33 +/- 0.22 ms, n = 112) mice. The results of these electrophysiological assessments imply that different demyelinating mechanisms, differentially affecting axon conduction, are present in the cuprizone-treated and shiverer mice, and may provide new insights to understanding the pathophysiology of demyelination in animal models in the CNS.

High-affinity choline uptake and acetylcholine-metabolizing enzymes in CNS white matter. A quantitative study.

The presence of nicotinic and muscarinic receptors suggests the occurrence of cholinergic neurotransmission in white matter; however no quantitative information exists on acetylcholine formation and breakdown in white matter. We compared white structures of pig brain (fimbria, corpus callosum, pyramidal tracts, and occipital white matter) to gray structures (temporal, parietal and cerebellar cortices, hippocampus, and caudate) and found that sodium-dependent, high-affinity choline uptake in white structures was 25-31% of that in hippocampus. White matter choline acetyltransferase activity was 10-50% of the hippocampal value; the highest activity was found in fimbria. Acetylcholine esterase activity in white structures was 20-25% of that in hippocampus. The caudate, which is rich in cholinergic interneurons, gave values for all three parameters that were 2.8-4 times higher than in hippocampus. The results suggest a certain capacity for cholinergic neurotransmission in central nervous white matter. The white matter activity of pyruvate dehydrogenase, which provides acetyl-CoA for acetylcholine synthesis, ranged between 33 and 50% of the hippocampal activity; the activity in the caudate was similar to that in hippocampus and the other gray structures, which was true also for other enzymes of glucose metabolism: hexokinase, phosphoglucomutase, and glucose-6-phosphate dehydrogenase. Acetylcholine esterase activity in white matter was inhibited by the nerve agent soman, which may help explain the reported deleterious effect of soman on white matter. Further, this finding suggests that acetylcholine esterase inhibitors used in Alzheimer's disease may have an effect in white matter.

MDMA treatment 6 months earlier attenuates the effects of CP-94,253, a 5-HT1B receptor agonist, on motor control but not sleep inhibition.

The possible long-term effects of the recreational drug "ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) on the function of 5-hydroxytryptamine-1B (5-HT(1B)) receptor in sleep and motor control were investigated using a selective 5-HT(1B) receptor agonist, 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyrinzidyl)-1H-pyrrolo([3,2-b])pyridine hydrochloride (CP-94,253; 5 mg/kg). CP-94,253 or vehicle was administered to freely moving rats pre-treated with MDMA (15 mg/kg) or vehicle 6 months earlier, and polygraphic recording for 24 h and motor activity measurements were performed. Active wake (AW), passive wake (PW), light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2), paradoxical sleep (PS), and diurnal rhythm were analyzed for the whole period. In additional, the EEG power spectrum was calculated for the second hour after the acute treatment for AW, PW, SWS-1, and SWS-2. 5-HT transporter (5-HTT) immunohistochemistry was measured in brain areas related to sleep and motor control 6 months after MDMA treatment. CP-94,253 increased AW and PW, decreased SWS-2 and PS, and altered parameters of diurnal rhythm in control animals. CP-94,253 decreased the EEG power spectra at higher frequencies. The effects of CP-94,253 on AW and diurnal rhythm were reduced or eliminated in MDMA-treated animals. MDMA treatment decreased 5-HTT fibre density in posterior hypothalamus, tuberomammillary nucleus, caudate putamen and ventrolateral striatum. These data suggest that long-term changes in 5-HT(1B) receptor function occur after serotonergic damage caused by a single dose of MDMA.

Prenatal exposure to a non-steroidal anti-inflammatory drug or saline solution impairs sciatic nerve morphology: a stereological and histological study.

The toxic effect of non-steroidal anti-inflammatory drugs (NSAIDs) during development has been widely investigated. While it has been shown that these drugs impair central nervous development and compromise the neural activity, the effects of these substances on the development of peripheral nerves are still not clarified. In the present study, sciatic nerves withdrawn from three experimental groups of 4-week-old rats, prenatally exposed to either saline solution, or diclofenac sodium, and controls not exposed to any substance, were evaluated in terms of axon number, cross-sectional area of axon and myelin sheet thickness as well as of the ultrastructure of nerve fibers. Comparisons of stereological estimations among these three groups showed that axon number and mean axon cross-sectional area, but not average myelin sheet thickness, were significantly decreased in rats that were exposed to both diclofenac sodium and also to the saline solution, in comparison of the control group. Electron microscope analysis revealed, in both treated groups, deterioration of myelin sheaths that was more pronounced in rats that were exposed to diclofenac sodium. Altogether, these findings show that the prenatal administration of both diclofenac sodium and saline solution impairs peripheral nervous system development, thus suggesting that this potential teratogenic effect should be also taken into consideration in the clinical use of these substances in pregnant patients.

Chemotherapy-induced peripheral neuropathy.

Recent advances in the development and administration of chemotherapy for malignant diseases have led to prolonged survival of patients and the promise of a return to normal lives. The cost of progress comes with a price, however, and the nervous system is frequently the target of therapy-induced toxicity. Unlike more immediate toxicities that affect the gastrointestinal tract and bone marrow, chemotherapy-induced neurotoxicity is frequently delayed in onset and may progress over time. In the peripheral nervous system, the major brunt of the toxic attack is directed against the peripheral nerve, targeting the neuronal cell body, the axonal transport system, the myelin sheath, and glial support structures, resulting in chemotherapy-induced peripheral neuropathy.