A preliminary description of the regeneration of optic nerve fibers in a reptile, Vipera aspis

Crushing or freezing the optic nerve of the viper leads initially to the anterograde degeneration of the optic nerve fibers and to an extensive retrograde demyelination process associated with the degeneration of some retinal ganglion cells. By the 45th postoperative day, regenerating unmyelinated axons can be identified in the damaged region of the optic nerve. These fibers reach the chiasm and the marginal optic tract by the third postoperative month. The radioautographic tracing method shows that some nuclei of the primary visual system begin to be reinnervated by about the 5th postoperative month; this reinnervation was not, however, completely restored in those specimens with the longest postoperative survival of 220 days.     

Neurotoxicity of antituberculous drugs in a patient without active tuberculosis

A 56-year old patient presented 3 months after initiation of an antituberculous regimen with Isoniacid (INH, 5 mg/kg daily), Ethambutol (20 mg/kg daily) and Rifampicin (675 mg daily) a mild sensory polyneuropahty and a bilateral retrobulbar neuritis wich progressed to a severe optic atrophy. Multiple hyperintense foci were detected with NMR-imaging in the cerebral white matter suggestive of demyelination. INH and Ethambutol are known for their neurotoxic effects but suggestion was made that neurologic signs may not be due to drug neurotoxicity but could be induced by immunological processes initiated by the tubercle bacillus. In the reported patient the suspected tuberculosis of the urogenital tract was never proved histologically. Most likely his neurological symptoms were therefore caused by the administration of INH and Ethambutol. Patients with a low serum zinc level and a slow, acetylation of INH are reported to be at special risk; both factors were present in our patient.

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Sommario Un uomo di 56 anni ha presentato, 3 mesi dopo l’inizio di una terapia antitubercolare con Isomiazide (INH, 5 mg/kg. al giorno), Etambutolo (20 mg/kg. al diì) e Rifamicina (675 mg. al dì), una polineuropatia sensitiva e una neurite retrobulare bilaterale esitata in una grave atrofia ottica. Alla NMR vennero evidenziati molti foci nell’ambito della sostanza bianca cerebrale suggestivi per una demielinizzazione. INH ed Etambutolo sono notoriamente neurotossici, ma si è ritenuto che i segni di sofferenza possono essere indotti da processi immunologici promossi dal bacillo turbercolare. Nel caso riportato la sospetta tubercolosi delle vie urinarie non è stata provata istologicamente. Quindi è più probabile che in questo caso i sintomi neurologici sono stati provocati dall’INH e dall’Etambutolo. I malati con livelli serici di zinco bassi e con una ridotta acetilazione di INH sono notoriamente a più alto rischio; nel nostro paziente questi due elementi erano presenti.

     

The optic nerve of the viper, Vipera aspis

A quantitative investigation of the optic nerves of eight adult vipers was carried out, both at the level of resolution of the light microscope by stereological methods, and at the level of resolution of the electron microscope. The majority (87%) of axons are myelinated, and the fibers are organized in fascicles; each bundle of axons is disposed around a central column of glial cells of which the greater proportion (62%) are oligodendrocytes, 33% are astrocytes and the remaining 5% are microglial cells. Estimations of the total number of fibers varied, from 5.37 X 10(4) to 6.96 X 10(4), among the eight specimens. The distribution of diameters of myelinated fibers is well characterized (chi 2 = 16.84, df = 22, 0.9 greater than p greater than 0.5) by a three-parameter lognormal distribution with a mean of 0.735 micron, standard deviation of 0.239 micron, and origin of 0.21 micron. Axon diameter is linearly related (r = 0.60) to the number of electron-dense layers in the myelin sheath. The diameters of unmyelinated fibers are distributed (chi 2 = 1.95, df = 4, 0.9 greater than p greater than 0.5) as a two-parameter lognormal distribution with mean of 0.25 micron and standard deviation of 0.067 micron. A surprisingly large number of myelinated fibers, apparently dispersed at random throughout the nerve, showed anomalies of myelination; two possible explanations, between which it is impossible to discriminate on the basis of the available data, are offered for this state of affairs.     

Neurotoxicity of Adriamycin and misonidazole in the mouse

The neurotoxicity of the anticancer drug adriamycin was investigated in the peripheral nerve of the mouse. Injection of adriamycin into the sciatic nerve resulted in biochemical and morphologic signs of severe axonal degeneration. The biochemical evidence was based on marked increases in lysosomal enzyme activity. Acid protease and N-acetylglucosaminidase remained elevated for more than 70 days after injecting the drug. In contrast, local injection of the radiation-sensitizing drug misonidazole into the peripheral nerve failed to increase lysosomal enzyme activity.     

Neurological complications of venomous snake bites: a review

Snake bite envenoming is a neglected tropical disease affecting millions of people living in the developing world. According to the offending snake species, the clinical picture may be dominated by swelling and soft tissue necrosis in the bitten limb, or by systemic or neurological manifestations. Serious neurological complications, including stroke and muscle paralysis, are related to the toxic effects of the venom, which contains a complex mixture of toxins affecting the coagulation cascade, the neuromuscular transmission, or both. Metalloproteinases, serine proteases, and C-type lentins (common in viper and colubrid venoms) have anticoagulant or procoagulant activity and may be either agonists or antagonists of platelet aggregation; as a result, ischemic or hemorrhagic strokes may occur. In contrast, the venom of elapids is rich in phospholipase A(2) and three-finger proteins, which are potent neurotoxins affecting the neuromuscular transmission at either presynaptic or post-synaptic levels. Presynaptic-acting neurotoxins (called β-neurotoxins) inhibit the release of acetylcholine, while post-synaptic-acting neurotoxins (called α-neurotoxins) cause a reversible blockage of acetylcholine receptors. Proper management of the envenomed patient, including prompt transport to the hospital, correction of the hemostatic disorder, ventilatory support, and administration of antivenom, significantly reduces the risk of neurological complications which, in turn, reduce the mortality and improve the functional outcome of survivors.     

Neurotoxicity of cancer chemotherapy

There is accumulating clinical evidence that chemotherapeutic agents induce neurological side effects, including memory deficits and mood disorders, in cancer patients who have undergone chemotherapeutic treatments. This review focuses on chemotherapy-induced neurodegeneration and hippocampal dysfunctions and related mechanisms as measured by in vivo and in vitro approaches. These investigations are helpful in determining how best to further explore the causal mechanisms of chemotherapy-induced neurological side effects and in providing direction for the future development of novel optimized chemotherapeutic agents.     

Neurotoxicity with combined administration of lithium and a neuroleptic

Case reports of neurotoxicity with lithium-neuroleptic combinations were reviewed with the objective of identifying the characteristics and predictors of the neurotoxic reaction. The investigation revealed that a reversible neurotoxic reaction characterized by organic psychopathological symptoms, extrapyramidal signs, cerebellar signs and fever may appear within a fortnight following the concurrent medication with lithium and neuroleptic(s) even though serum lithium levels are maintained at therapeutic or subtherapeutic values.     

Neurotoxicity of the pesticide rotenone on neuronal polarization: a mechanistic approach

Neurons are the most extensive and polarized cells that display a unique single long axon and multiple dendrites, which are compartments exhibiting structural and functional differences. Polarity occurs early in neuronal development and it is maintained by complex subcellular mechanisms throughout cell life. A well-defined and controlled spatio-temporal program of cellular and molecular events strictly regulates the formation of the axon and dendrites from a non-polarized cell. This event is critical for an adequate neuronal wiring and therefore for the normal functioning of the nervous system. Neuronal polarity is very sensitive to the harmful effects of different factors present in the environment. In this regard, rotenone is a crystalline, colorless and odorless isoflavone used as insecticide, piscicide and broad spectrum pesticide commonly used earlier in agriculture. In the present review we will summarize the toxicity mechanism caused by this pesticide in different neuronal cell types, focusing on a particular biological mechanism whereby rotenone could impair neuronal polarization in cultured hippocampal neurons. Recent advances suggest that the inhibition of axonogenesis produced by rotenone could be related with its effect on microtubule dynamics, the actin cytoskeleton and their regulatory pathways, particularly affecting the small RhoGTPase RhoA. Unveiling the mechanism by which rotenone produces neurotoxicity will be instrumental to understand the cellular mechanisms involved in neurodegenerative diseases influenced by this environmental pollutant, which may lead to research focused on the design of new therapeutic strategies.     

Neurotoxicity of quinolinate in the rat nucleus basilis magnocellularis

Injections of quinolinic acid (QUIN) alone or combinations of QUIN with dipicolinic acid, Mg2+ or 3,4-diaminopyridine were made into the nucleus basalis magnocellularis of the rat. Choline acetyltransferase activity in the cortex decreased following injections of QUIN and this was antagonized by co-injections of QUIN with dipicolinic acid or Mg2+. Co-injections of QUIN with 3,4-diaminopyridine increased the neurotoxicity of quinolinic acid, while diaminopyridine alone was not toxic.     

Neurotoxicity of the pyrimidine synthesis inhibitor N-phosphonoacetyl-L-aspartate

PALA (N-phosphonoacetyl-L-aspartate) impairs de novo pyrimidine biosynthesis by inhibiting the enzyme aspartate transcarbamylase. During cancer chemotherapy trials the drug was given by weekly intravenous infusion. Seizures developed in 9 (11%) of the first 80 patients to receive a total dose of 9 gm/m² or more. Seven of the affected patients had structural brain lesions; they developed seizures at a lower total dose (median of 16.4 gm/m²) than the 2 patients without clinically detectable brain lesions (115 to 130 gm/m²). Reversible encephalopathy was observed in 6 (7.5%) additional patients without clinically detectable cause other than PALA. Both seizures and encephalopathy began after the second dose of PALA or later. Experiments in rats demonstrated similar delayed-onset seizures after two or three combined systemic and intracerebral doses of PALA at 4-day intervals. Concurrent administration of uridine or carbamyl aspartate prevented the development of seizures in rats, indicating that pyrimidine starvation of the central nervous system was responsible for PALA neurotoxicity.     

Neurotoxicity of topically applied hexachlorophene in the young rat.

Young rats 6 to 22 days of age are extremely susceptible to the neurotoxic effects of hexachlorophene given as a daily bath of undiluted antiseptic detergent containing 3% hexachlorophene (pHiso-Hex). At this age, most rats are clinically and histologically damaged by as few as two daily baths. Younger rats are relatively resistant, probably because they have less myelin to be affected; older rats cannot be poisoned by this route, probably because the more mature liver excretes the drug more effectively. Age-dose-response curves in rats are similar to those in humans. This experimental model is potentially useful in defining other characteristics of this drug.     

Neurotoxicity of traffic-related air pollution

The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250–300 μg/m³ for 6 h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.     

Neurotoxicity of dipiperidinoethane due to in vivo conversion to a selective cholinesterase inhibitor

Dipiperidinoethane (DPE) administration produces seizures and CNS lesions. Here we elucidate the cholinergic origin of DPE toxicity. DPE is both an acetylcholinesterase (AChE) inhibitor and a muscarinic antagonist. This dual action negates most of the toxic effects of the compound in vivo. The neurotoxicity is believed to arise from oxidative conversion to DPE-N-oxide, which selectively inhibits AChE. Cytotoxicity does not involve muscarinic neurons, since binding parameters were unchanged following in vivo exposure.     

Neurotoxicity of intrathecal gentamicin: a case report and experimental study

Distinctive lesions occurred in the brainstem of a 59-year-old patient who had had recent Pseudomonas aeruginosa meningitis treated with parenteral and intrathecal gentamicin sulfate. The lesions were multiple, minute, and discrete, and were characterized by loss of axons, spongiosis, axonal swelling with frequent calcification, loss of astroglia and oligodendroglia, and slight inflammatory response. These lesions were restricted to the myelinated fiber bundles of the pons and mesencephalon. Because similar lesions can occur with other intrathecally administered medications and emboli to the brain, an experimental study in rabbits was done. Similar lesions were produced in normal adult rabbits after a single intracisternal injection of gentamicin sulfate with or without preservative at doses equivalent to 50 and 100 times the human therapeutic dose. Lesions were not seen after injection of normal saline, preservative, or gentamicin sulfate with preservative at doses equivalent to 1 and 10 times the human therapeutic dose. A direct relationship was observed between the cerebrospinal fluid concentrations of gentamicin, brain tissue concentrations of gentamicin, and occurrence of the lesions.     

Unilateral Contrast Neurotoxicity as a Stroke Mimic After Cerebral Angiogram

Contrast neurotoxicity (CN) following exposure to iodinated contrast is uncommon, and usually presents as cortical blindness due to bilateral occipital lobe involvement. Unilateral cortical dysfunction due to CN could mimic an acute stroke and has been rarely described. We report the case of an 89‐year‐old female who developed a transient dense/complete left homonymous‐hemianopsia and left‐sided tactile extinction after undergoing a right internal carotid (ICA) artery rotational angiogram with a standard high‐volume iodinated contrast injection for 3D visualization a 6×4‐mm right posterior communicating artery aneurysm with a fetal posterior cerebral artery (PCA) incorporated in the neck. This was associated with transient fullness and loss of gray‐white matter differentiation in the right occipital and parietal lobes. The potential mechanism of CN in our case was the injection of a high volume of contrast in the ICA for the rotational angiogram. The presence of a right fetal PCA possibly allowed the contrast to reach the right occipital lobe. CN manifesting as an acute focal neurologic syndrome should be considered in the setting of recent iodinated contrast exposure.     

Neurotoxicity of the Putative Transmembrane Domain of the Prion Protein

It has been shown recently that the generation of an abnormal transmembrane form of the prion protein (^CtmPrP) is involved in the neurodegeneration process during inherited and infectious prion diseases but a causative relationship has never been established. We wanted to know if and how the proposed transmembrane domain of PrP could induce neuronal dysfunction. Thus, we investigated the neurotoxic properties of two peptides whose sequences are encompassed within this domain. We show that PrP peptides 118–135 and 105–132 as well as an amidated more soluble peptide 105–132 induce the death of pure cortical neurons originating from normal and PrP knockout mice. This can be correlated with the high propensity of these peptides to insert stably into and to destabilize cell membranes. Through this study, we have identified a novel mechanism of neurotoxicity for PrP, which directly involves membrane perturbation; this mechanism is independent of fibril formation and probably corresponds to the effect of the transmembrane insertion of ^CtmPrP.