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Introduction: Upper-limb symptoms are often reported in the context of chemotherapy-induced peripheral neurotoxicity (CIPN), but objective quantification of functional deficits is often lacking. We examined and compared a range of neurophysiological and functional assessments of the upper-limb in the assessment of CIPN severity., Methods: Cross-sectional assessment of neurotoxic chemotherapy-treated patients was undertaken using patient-reported and clinically-graded CIPN measures. Upper-limb functional assessments comprised of assessing fine motor skills, sensory perception, and neurophysiological measures of the median nerve. Group comparisons between participants who reported absence or presence of upper-limb functional deficits were investigated., Results: 60 participants who were 11.5 (IQR = 4.0-26.0) months post-neurotoxic chemotherapy treatment reported CIPN. 65% (n = 39) reported upper-limb CIPN symptoms. Reduction in fine motor skills, sensory perception and median nerve SNAP amplitudes were associated with higher CIPN severity. Participants who self-reported presence of upper-limb functional deficits had worse CIPN severity across all measures, compared to participants who reported no upper-limb functional deficits., Conclusions: Participants who reported upper-limb symptoms and functional deficits had worse CIPN severity and quality-of-life. There is a high burden of upper-limb dysfunction long after neurotoxic chemotherapy treatment cessation. Focus on research into supportive care and rehabilitation options to improve upper-limb function is warranted to improve patient quality-of-life., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Objective: Immunotherapeutic approaches have revolutionized cancer treatment with immune checkpoint inhibitors and adoptive T-cell therapy now approved to treat a variety of solid and hematologic malignancies. This article summarizes the distinctive neurologic side effects of these therapies as well as their management., Latest Developments: Neurologic immune-related adverse events are rare but potentially serious complications of immune checkpoint inhibitors. Both peripheral and central nervous system disorders have been described, often necessitating a pause or cessation of immunotherapy. Immune effector cell-associated neurotoxicity syndrome is a potentially serious complication of chimeric antigen receptor T-cell therapy. While symptoms may be mild and self-limited, delirium, encephalopathy, seizures, focal neurologic deficits, and fulminant cerebral edema can be seen. Close neurologic monitoring is imperative. The mainstay of treatment for neurologic complications includes high-dose corticosteroids, although other immunomodulatory strategies may be used in severe or refractory cases., Essential Points: The spectrum of neurologic complications of cancer immunotherapy is broad, encompassing both central and peripheral nervous system disorders, indolent as well as fulminant clinical presentations, and wide-ranging severity with variable response to treatment. Early identification and multidisciplinary management are crucial to balance neurologic recovery and antitumor control., (Copyright © 2023 American Academy of Neurology.)

Chimeric antigen receptor (CAR) T cell therapy targeting CD-19 has revolutionized the treatment of refractory B-cell malignancies. However, patients undergoing this therapy face an increased risk of infections due to compromised immune function, lymphodepleting chemotherapy, hospitalization, and therapy-related complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Patients with systemic corticosteroid use, low immunoglobulin levels, and severe CRS, are at higher risk of infection. This review article highlights the spectrum of infections encountered in CAR T cell therapy, including bacterial, viral, and fungal infections. Following consensus guidelines for vaccination and immunoglobulin replacement is recommended. Clear criteria for antibiotic usage and vaccinating household members against respiratory viruses are crucial. Understanding the risk factors, spectrum of infections, and implementing appropriate prophylactic measures are essential to optimize outcomes in patients undergoing CAR T cell therapy. By prioritizing infection prevention strategies, healthcare professionals can effectively improve patient care., (©The Author 2023. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

Sodium valproate is a commonly prescribed anticonvulsant medication; however, it can cause uncommon side effects such as hyperammonaemia and encephalopathy. We present the case of a male in his early 50s brought to the emergency department after being found collapsed by his wife, with an empty bottle of sodium valproate tablets. The patient developed hyperammonaemic encephalopathy due to sodium valproate overdose and was treated with supportive care and renal replacement therapy. This case highlights the importance of recognising the potential complications of sodium valproate and its prompt treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting toxicity of cancer treatment causing functional impairment and impacting quality of life. Effective prevention and treatment of CIPN are lacking, and CIPN risk factors remain ill-defined. Metabolic syndrome and associated conditions have emerged as potential risk factors, due to their high prevalence and independent association with nerve dysfunction. This systematic review aimed to investigate the association between these common metabolic-lifestyle factors and CIPN., Methods: Searches were undertaken using Medline, Embase, CINAHL, Scopus, and Web of Science databases, with additional studies identified from bibliographic references cited by original and review articles. Articles that analyzed metabolic-lifestyle risk factors associated with CIPN for patients treated with platinum- or taxane-based chemotherapy were included., Results: Searches identified 6897 titles; 44 articles had full text review, with 26 studies included. Overall incidence of neuropathy ranged from 16.9 to 89.4%. Obesity had the most consistent patient-oriented evidence as a risk factor for CIPN, with moderate evidence suggesting diabetes did not increase CIPN incidence or severity. A limited number of studies supported an association with low physical activity and greater CIPN risk., Conclusions: Comorbidities and lifestyle factors, particularly obesity and low physical activity, may contribute to the development of CIPN. The implementation of sensitive outcome measures in large-scale clinical trials is required to further elucidate CIPN risk factors and evaluate if changes in lifestyle would improve long-term CIPN outcomes for cancer survivors., Implications for Cancer Survivors: Better understanding of CIPN risk profiles may inform personalized medicine strategies and help elucidate pathophysiological mechanisms which could be targeted for neuroprotection., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Background: With the increase in the number of people exposed to anesthetic gases, there is a critical need to examine the prevalence of neurotoxic symptoms in these individuals using reliable tools. The aim of this study was to evaluate the psychometric characteristics of EUROQUEST questionnaire and to measure the rate of neurotoxic symptoms in the anesthesiology personnel., Methods: This research was a cross-sectional study. This study was a cross-sectional one. Participants included 404 personnel of the operating room in western Iran. EUROQUEST questionnaire was translated into Persian and used to measure the rate of neurotoxic symptoms. Reliability of the questionnaire was examined by Cronbach's alpha, while face and construct validities were evaluated using SPSS 16 (SPSS Inc., Chicago, IL, USA) and AMOS 18 (IBM, Chicago, IL, USA) software., Results: The results indicated that EUROQUEST questionnaire had acceptable reliability and validity. The most prevalent symptoms were observed in memory and concentration, fatigue, and sleepiness. The prevalence of fatigue was higher than other dimensions, with 28% of participants in the third and fourth quartiles. Also, there was no relationship between symptoms and work experience., Conclusions: EUROQUEST questionnaire can be applied in studies of the neurotoxic symptoms. The study of the prevalence of symptoms also indicated that most participants complained about memory and concentration, fatigue, and sleepiness, and these symptoms were observed in all individuals regardless of their work experience.

Aluminium (Al) is a potent neurotoxic metal known to cause neurodegeneration. Al exposure causes oxidative stress by accumulation of reactive oxygen species, followed by the activation of neuronal cell death in the brain. Asiatic acid (AA), the major bioactive compound of Centella asiatica (a medicinal plant), act as multifunctional drug as well as an antioxidant. Thus, the present study aimed to investigate the potential neuroprotective effect of AA against Al neurotoxicity. Rats were orally administered aluminium chloride (AlCl 3 ; 100 mg/kg b. wt.) dissolved in distilled water for 8 weeks or AA (75 mg/kg b. wt.) in combination with AlCl 3 . The results showed that AlCl 3 -intoxication causes significant impairment of memory, enhances anxiety-like behavior, acetyl cholinesterase (AChE) activity, malondialdehydes (MDA) level, and concomitant decrease in the activities of superoxide dismutase (SOD) and catalase (CAT) in the cortex and hippocampus regions of rat brain. In addition, AlCl 3 -intoxication enhanced neuronal loss and reactive astrogliosis in both regions. However, co-administration of AA with AlCl 3 significantly attenuated the behavioral alterations, restored SOD and CAT activities, while reduced AChE activity and MDA content. Further, the study demonstrated that AA attenuates neuronal loss and reactive astrogliosis in rat brain. In conclusion, the study suggests that AA protects rat brain from Al neurotoxicity by inhibiting oxidative stress, neuronal loss and reactive astrogliosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The main component of the gas in the fish storage tank is hydrogen sulfide. Hydrogen sulfide poisoning is a common occupational chemical poisoning among fishermen in summer, and acute hydrogen sulfide poisoning can manifest as toxic encephalopathy. This paper analyzes a patient with delayed encephalopathy suspected of acute hydrogen sulfide poisoning. The patient was unconscious for 18 days after waking up for 5 days after acute hydrogen sulfide poisoning. After waking up again, there were symptoms such as decreased limb muscle strength, ataxia, swallowing, dysarthria, and the clinical characteristics were significantly different from those of delayed encephalopathy caused by acute carbon monoxide poisoning, such as decreased cognitive function and damage to extrapyramidal system.

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual's vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/m 2 ) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment., Methods: Three hundred seventy-nine cancer survivors were assessed 5 (IQR 3-5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/m 2 ) were compared to those within the normal BMI range (< 25 kg/m 2 ). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity., Results: Most patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p < .05). In multivariate linear regression, older age (B = .088, 95%CI = .053-.122, p < .001), larger waist circumference (B = .030, 95%CI = .001-.059, p < .05), and larger BSA (B = 2.41, 95%CI = .34-04.48, p < .05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models., Conclusions: Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient's general and abdominal obesity status may aid in formulating personalized treatment., Implications for Cancer Survivors: Identifying routinely measured patient characteristics which may contribute to an individual's CIPN risk profile could assist with informing treatment decisions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

The main pathological changes that occur in delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) are extensive demyelination of brain white matter and neuron damage. Previous studies suggested that demyelination and neuron injury are related to activating the Rho/ROCK signaling pathway. Inhibition of the Rho/ROCK signaling pathway can alleviate neuron injury and promote myelin repair. This study utilized a DEACMP model in which rats were prepared by space injection of CO gas intraperitoneally (CO group), and the association between the Rho/ROCK signaling pathway and DEACMP was investigated. The ROCK2 kinase inhibitor Y-27632 was used to prevent the effects of the DEACMP model to elucidate its protective mechanism. The results demonstrated that the cognitive and motor functions were significantly impaired, and the GFAP, NSE, RhoA, and ROCK2 protein levels were significantly increased in the CO group within three weeks after the model was established. After Y-27632 intervention, the cognitive and motor functions of the CO+Y-27632 group were significantly improved within three weeks after the model was established. In the CO+Y-27632 group, the RhoA, ROCK2, GFAP, and NSE (indicating neuron injury) protein levels decreased significantly, and the MBP protein levels (indicating myelin repair) increased significantly within three weeks after the model was established. These results suggested that the pathogenesis of DEACMP was associated with activation of the Rho/ROCK pathway and that Y-27632 inhibited ROCK2 kinase activity in the CO exposed rats, resulting in improved behavioral deficits, reduced neuron damage, and promotion of myelin repair. Therefore, Y-27632 might be a potentially effective drug for the treatment of DEACMP-induced brain damage., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: The present review aims to present and discuss the consistent and inconsistent evidence regarding the associations between mitochondrial dysfunction and several neuropathic models, including trauma-induced, chemotherapy-induced, diabetes-induced and HIV-associated sensory neuropathy., Methods: The searching strategy and inclusion criteria for this review are all research articles in the PubMed database published before July 2019. We used the search terms 'mitochondria' and 'neuropathy' for the present review and non-English articles were excluded., Results: Damage to mitochondria via trauma, chemotherapy drugs, hyperglycaemia and HIV infection has been widely discussed to play an important role in the pathogenesis of neuropathy. Several mechanisms of mitochondrial damages have been proposed., Conclusion: The damage of mitochondria results in cellular apoptosis, which appears to be one of the key factors in the pathogenesis of neuropathy. Novel therapeutic strategies targeting mitochondria could be a potential therapeutic target in neuropathy.

Introduction: Preclinical studies suggest that inhalational anesthetics may induce neuropathology changes in the nigrostriatal system, leading to development of α-synucleinopathies. We explored the role of general anesthesia in the development of Parkinson disease (PD) and other α-synucleinopathies., Methods: All α-synucleinopathy cases in Olmsted County, Minnesota, from January 1991, to December 2010, were identified from diagnostic codes, and then reviewed for type and index date of diagnosis. Cases were matched by sex and age (±1 year) to a referent control, a resident living in Olmsted County, and free of α-synucleinopathies before the index date (year of onset of the α-synucleinopathy). Medical records of both cases and controls were reviewed for lifetime exposure to anesthesia prior to the index date., Results: A total of 431 cases with clinically defined α-synucleinopathies were identified. Of these, 321 (74%) underwent 1,069 procedures under anesthesia before the diagnosis date, and in the control group, 341 (79%) underwent 986 procedures. When assessed as a dichotomous variable, anesthetic exposure was not significantly associated with α-synucleinopathies (odds ratio [OR], 0.75; 95% CI, 0.54-1.05; P=.094). No association was observed when anesthetic exposure was quantified by the number of exposures (OR, 0.64, 0.89, and  0.74, for 1, 2-3, and ≥4 exposures, respectively, compared to no exposure as the reference; P=.137) or quantified by the cumulative duration of exposure assessed as a continuous variable (OR, 1.00; 95% CI, 0.97-1.02 per 1-h increase of anesthetic exposure; P=.776)., Conclusions: We did not observe a significant association between exposure to general anesthesia and risk for the development of α-synucleinopathies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl 3 ), which mimics the sporadic form of Alzheimer's disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl 3 -exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl 3 -induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl 3 -exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD.

New toxins are emerging all the time. In this article, the authors review common toxins that cause seizure, their mechanisms, associated toxidromes, and treatments. Stimulants, cholinergic agents, gamma-aminobutyric acid antagonists, glutamate agonists, histamine and adenosine antagonists, and withdrawal states are highlighted. Understanding current mechanisms for common toxin-induced seizures can promote understanding for future toxins and predicting if seizure may occur as a result of toxicity., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Toxins identified as causing parkinsonism and being related to overall idiopathic Parkinson disease risk range from heavy metals to pesticides to contaminants in synthetic heroin. Several described in this article exhibit significant oxidative stress on neurons of the central nervous system and have a particular predilection toward damage of dopaminergic neurons. Although many of these toxins have well-established connections with Parkinson disease risk, a few continue to be studied with data still being produced. The parkinsonisms caused by these agents have variable responses to dopaminergic therapies. This article discusses manganese, mercury, MPTP, organochlorines, organophosphates, paraquat, rotenone, and Agent Orange., Competing Interests: Disclosure The views expressed in this article are those of the author and do not reflect the official policy of the Department of Army/Navy/Air Force, Department of Defense, or US Government., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Several different types of exposure have the potential to produce olfactory and gustatory deficits related to neurotoxicity. Although the literature contains relatively few studies of such chemoreceptive dysfunction in the context of toxic exposure, this review explores the strength of such published associations. Several studies collectively demonstrated moderately strong evidence for an association between manganese dust exposure and olfactory deficits. Evidence of associations between individual chemicals, therapeutics, and composites, such as World Trade Center debris, and olfactory and gustatory deficits remains limited or mixed. Further need for controlled studies for clinical management, exposure limits, and policy development is identified., Competing Interests: Disclosure The authors have no commercial or financial conflicts of interest to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)

CYP2D6 metabolically inactivates several neurotoxins, including beta-carbolines, which are implicated in neurodegenerative diseases. Variation in CYP2D6 within the brain may alter local inactivation of neurotoxic beta-carbolines, thereby influencing neurotoxicity. The beta-carboline harmine, which induces hypothermia and tremor, is metabolized by CYP2D6 to the non-hypothermic/non-tremorgenic harmol. Transgenic mice (TG), expressing human CYP2D6 in addition to their endogenous mouse CYP2D, experience less harmine-induced hypothermia and tremor compared with wild-type mice (WT). We first sought to elucidate the role of CYP2D in general within the brain in harmine-induced hypothermia and tremor severity. A 4-h intracerebroventricular (ICV) pretreatment with the CYP2D inhibitor propranolol increased harmine-induced hypothermia and tremor in TG and increased harmine-induced hypothermia in WT. We next sought to specifically demonstrate that human CYP2D6 expressed in TG brain altered harmine response severity. A 24-h ICV propranolol pretreatment, which selectively and irreversibly inhibits human CYP2D6 in TG brain, increased harmine-induced hypothermia. This 24-h pretreatment had no impact on harmine response in WT, as propranolol is not an irreversible inhibitor of mouse CYP2D in the brain, thus confirming no off-target effects of ICV propranolol pretreatment. Human CYP2D6 activity in TG brain was sufficient in vivo to mitigate harmine-induced neurotoxicity. These findings suggest that human CYP2D6 in the brain is protective against beta-carboline-induced neurotoxicity and that the extensive interindividual variability in CYP2D6 expression in human brain may contribute to variation in susceptibility to certain neurotoxin-associated neurodegenerative disorders.

Purpose of Review: Vitamin and mineral deficiencies, neurotoxins, and, particularly, prescription medications, are some of the most common causes of peripheral neuropathy. Recognition and prompt treatment of these neuropathies require a high index of suspicion and an accompanied detailed history. This article provides a comprehensive approach and list of items that must be considered in the setting of new-onset neuropathy., Recent Findings: Although many of the neuropathies described in this article have decreased in prevalence in developed countries because of public health interventions and occupational/environmental regulations, new causes for this class of neuropathy continue to be uncovered., Summary: The peripheral nervous system is susceptible to a broad array of metabolic and toxic abnormalities, which most often lead to a length-dependent sensory-predominant axonal peripheral neuropathy. A careful history accompanied by recognition of multisystem clues can increase recognition of these neuropathies, which is important as many have specific treatments that may either improve the neuropathy or halt its progression.

We report a case of cefepime neurotoxicity characterised by myoclonic status epilepticus with coma, in a context of acute renal failure and requiring one discontinuous conventional haemodialysis. Cefepime is a fourth-generation broad-spectrum cephalosporin mainly used to treat hospital-acquired Gram-negative infections. Acute neurotoxicity is an increasingly reported adverse effect which occurs predominantly in patients with renal impairment. Renal replacement therapy has been proposed to treat this condition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Oxaliplatin-induced neurotoxicity can be a dose-limiting side effect to effective chemotherapy. Acute hyperexcitability causes cold-evoked sensory and motor symptoms, which resemble neuromyotonia. An accessible and non-invasive technique for early detection could help select patients for potential treatments. We assessed the use of a simple surface electromyography (sEMG) in patients directly after oxaliplatin infusion., Methods: In patients with colorectal cancer, acute neurotoxicity was evaluated by means of a physical examination, a questionnaire, and sEMG directly after the second and fourth cycle of oxaliplatin. Questionnaires were also assessed 1 day after infusion., Results: 14 patients were measured after the second cycle and 8 patients were also measured after the fourth cycle of oxaliplatin. All patients reported to a variable degree oxaliplatin induced neurotoxicity symptoms: sensitivity to touching cold or swallowing cold items were reported as most severe. Clinical signs of hyperexcitability were observed in 55% of the measurements. Spontaneous activity compatible with neuromyotonia was observed in 82% of the sEMG recordings., Conclusions: Patient reported symptoms, physical examination and simple sEMG are complementary measurements to detect acute oxaliplatin induced neurotoxicity. After further validation, sEMG recording can be used as a simple objective screenings tool to detect nerve hyperexcitability directly after oxaliplatin administration., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Methamphetamine (METH) is an illicit psychostimulant that is subject to abuse worldwide. While the modulatory effects of METH on dopamine neurotransmission and its neurotoxicity in the central nervous system are well studied, METH's effects on modulating microglial neuroimmune functions and on eliciting neuroinflammation to affect dopaminergic neurotoxicity has attracted considerable attention in recent years. The current review illuminates METH-induced neurotoxicity from a neuropathological perspective by summarizing studies reporting microglial activation after METH administration in rodents. Assessing microglial reactivity in terms of the cells' morphology and immunophenotype offers an opportunity for comprehensive and objective assessment of the severity and nature of METH-induced neuronal perturbations in the CNS and can thus contribute to a better understanding of the nature of METH toxicity. We reach the conclusion here that the intensity of microglial activation reported in the majority of animal models after METH administration is quite modest, indicating that the extent of dopaminergic neuron damage directly caused by this neurotoxicant is relatively minor. Our conclusion stands in contrast to claims of excessive and detrimental neuroinflammation believed to contribute and exacerbate METH neurotoxicity. Thus, our analysis of published studies does not support the idea that suppression of microglial activity with anti-inflammatory agents could yield beneficial effects in terms of treating addiction disorders.

In this article the neurotoxic disorders appearing in patients exposed to organophosphorus pesticides and known mechanisms involved are reviewed. Organophosphorus compounds cause four main neurotoxic effects in humans: the cholinergic syndrome, the intermediate syndrome, organophosphate-induced delayed polyneuropathy and chronic organophosphate-induced neuropsychiatric disorder. Compared to the cholinergic syndrome, that causes millions of cases of poisoning with fatality of more than 15% each year, other disorders involve much smaller number of patients. Possible link of exposure to organophosphorus pesticides with neurodegenerative diseases, dementia, attention deficit hyperactivity disorder and Parkinson's disease in man is also approached. This article is focused on neurotoxic disorders appearing after acute and chronic exposure to organophosphates with emphasis on molecular mechanisms, clinical presentation, pathogenesis, and possibilities for prevention/medical treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Oxaliplatin-induced neurotoxicity is the single main dose-limiting factor in the treatment of colorectal cancer. The degree of neurotoxicity may be either acute and reversible or observed as cumulative and chronic peripheral nerve damage leading to peripheral neuropathy (PNP), walking difficulties, extremity hypersensitivity, tingling and numbness, and increased pain sensation., Aim: The aim of this paper is to determine and compare the ratio of clinical versus subclinical PNP cases in colorectal patients who underwent oxaliplatin treatment., Materials and Methods: Thirty-two colorectal cancer patients were enrolled in the study. Patients received chemotherapy either as folinic acid and 5-fluorouracil and oxaliplatin or capecitabine and oxaliplatin regimen. Electroneurophysiological tests were performed before the treatment and after the 4 th cycle when the risk of peripheral nerve damage increases. All patients were subject to a standard neurological examination and a semi-structured questionnaire interview., Results and Discussion: Following oxaliplatin treatment, 21 (66.6%) of all patients presented neurological symptoms and/or electrophysiologically measured signs of PNP; of those, 7 patients (33.4%) displayed only electrophysiological changes and the remaining 14 patients (66.6%) presented fully symptomatic PNP - 4 patients were new neuropathy cases while the other 10 patients were previously diagnosed with PNP and showed signs of further neuronal deterioration and progressing sensory and motor dysfunction., Conclusion: Our study lays ground for further larger scale longitudinal studies on oxaliplatin neurotoxicity and its prevention. We believe that early diagnosis of oxaliplatin-induced neurotoxicity is essential in the prevention of irreversible nerve damage and should be prioritized when assessing and evaluating treatment so that adequate adjustment may be made., Competing Interests: There are no conflicts of interest

Background: Melatonin is a well-known potent endogenous antioxidant pharmacological agent with significant neuroprotective actions. Here in the current study, we explored the nuclear factor erythroid 2-related factor 2 (Nrf2) gene-dependent antioxidant mechanism underlying the neuroprotective effects of the acute melatonin against acute ethanol-induced elevated reactive oxygen species (ROS)-mediated neuroinflammation and neurodegeneration in the developing rodent brain., Methods: In vivo rat pups were co-treated with a single dose of acute ethanol (5 g/kg, subcutaneous (S.C.)) and a single dose of acute melatonin (20 mg/kg, intraperitoneal (I.P.)). Four hours after a single S.C. and I.P. injections, all of the rat pups were sacrificed for further biochemical (Western blotting, ROS- assay, LPO-assay, and immunohistochemical) analyses. In order to corroborate the in vivo results, we used the in vitro murine-hippocampal HT22 and microglial BV2 cells, which were subjected to knockdown with small interfering RNA (siRNA) of Nrf2 genes and exposed with melatonin (100 μM) and ethanol (100 mM) and proceed for further biochemical analyses., Results: Our biochemical, immunohistochemical, and immunofluorescence results demonstrate that acute melatonin significantly upregulated the master endogenous antioxidant Nrf2 and heme oxygenase-1, consequently reversing the acute ethanol-induced elevated ROS and oxidative stress in the developing rodent brain, and in the murine-hippocampal HT22 and microglial BV2 cells. In addition, acute melatonin subsequently reduced the activated MAPK-p-P38-JNK pathways and attenuated neuroinflammation by decreasing the expression of activated gliosis and downregulated the p-NF- K -B/p-IKKβ pathway and decreased the expression levels of other inflammatory markers in the developing rodent brain and BV2 cells. Of note, melatonin acted through the Nrf2-dependent mechanism to attenuate neuronal apoptosis in the postnatal rodent brain and HT22 cells. Immunohistofluorescence results also showed that melatonin prevented ethanol-induced neurodegeneration in the developing rodent brain. The in vitro results indicated that melatonin induced neuroprotection via Nrf2-dependent manner and reduced ethanol-induced neurotoxicity., Conclusions: The pleiotropic and potent neuroprotective antioxidant characteristics of melatonin, together with our in vivo and in vitro findings, suppose that acute melatonin could be beneficial to prevent and combat the acute ethanol-induced neurotoxic effects, such as elevated ROS, neuroinflammation, and neurodegeneration in the developing rodent brain.

Purpose: Limited information is available on the impact of chemotherapy (CTX)-induced neurotoxicity on adult survivors' symptom experience and quality of life (QOL). Purposes were to describe occurrence of hearing loss and tinnitus and evaluate for differences in phenotypic characteristics and measures of sensation, balance, perceived stress, symptom burden, and QOL between survivors who received neurotoxic CTX and did (i.e., neurotoxicity group) and did not (i.e., no neurotoxicity group) develop neurotoxicity. Neurotoxicity was defined as the presence of chemotherapy-induced neuropathy (CIN), hearing loss, and tinnitus. Survivors in the no neurotoxicity group had none of these conditions., Methods: Survivors (n = 609) completed questionnaires that evaluated hearing loss, tinnitus, stress, symptoms, and QOL. Objective measures of sensation and balance were evaluated., Results: Of the 609 survivors evaluated, 68.6% did and 31.4% did not have CIN. Of the survivors without CIN, 42.4% reported either hearing loss and/or tinnitus and 48.1% of the survivors with CIN reported some form of ototoxicity. Compared to the no neurotoxicity group (n = 110), survivors in the neurotoxicity group (n = 85) were older, were less likely to be employed, had a higher comorbidity burden, and a higher symptom burden, higher levels of perceived stress, and poorer QOL (all p < .05)., Conclusions: Findings suggest that CIN, hearing loss, and tinnitus are relatively common conditions in survivors who received neurotoxic CTX., Implications for Cancer Survivors: Survivors need to be evaluated for these neurotoxicities and receive appropriate interventions. Referrals to audiologists and physical therapists are warranted to improve survivors' hearing ability, functional status, and QOL.

The pathogenesis of Alzheimer's disease (AD) has still not been fully elucidated, however it is thought that the build up of amyloid plaque at least partially causes the symptoms of AD. MicroRNAs (miRNAs) are endogenous non‑coding small RNA molecules that regulate the expression and degradation of proteins. The present study induced symptoms of AD in mice via intraventricular injection of amyloid‑β 1‑42 (Aβ1‑42), which decreased levels of miR‑107. However, miR‑107 levels increased following administration of miR‑107 mimic, a double‑stranded RNA molecule designed to imitate the native miRNA. Intraventricular injection of Aβ1‑42 aggregates led to spatial memory impairments, inhibited hippocampal long‑term potentiation (LTP) and resulted in the loss of pyramidal cells in the CA1 region of the hippocampus. The miR‑107 mimic reversed the impairments of spatial memory and LTP and the loss of pyramidal neurons caused by Aβ neurotoxicity. Furthermore, the miR‑107 mimic reversed the Aβ‑induced increase in Aβ1‑42 and phosphorylated Tau levels. Critically, Aβ1‑42 injection decreased levels of brain‑derived neurotrophic factor and reduced the phosphorylation of tyrosine receptor kinase B and protein kinase B; these changes were reversed following treatment with the miR‑107 mimic. Collectively, these results demonstrated that miR‑107 may be a potential target for the treatment of AD.

The cerebellum is a brain region which is particularly susceptible to intoxication. Clinical presentation is heterogeneous. It is often considered that elderly patients and patients presenting pre-existing structural lesions of the posterior fossa are particularly at risk of developing a toxic-induced cerebellar syndrome (TOICS). However, TOICS may occur at any age, including in utero. Indeed, the cerebellum is highly vulnerable during neurodevelopment. Amongst cerebellotoxic agents, ethanol is the most commonly implicated. The vermis is a privileged target. Ethanol exerts toxic effects upon neurons, glia (especially astrocytes and oligodendrocytes), and myelin sheaths. Prenatal alcohol exposure causes teratogenic effects on the developing cerebellum, impeding neuronal migration and differentiation. In adults, cerebellar ataxia is a major feature of both acute and chronic ethanol intoxication. Wernicke encephalopathy is a medical emergency characterized by a triad of ophthalmoplegia, ataxia, and impaired mental status. It requires the immediate administration of high doses of thiamine by the intravenous route. The following drugs may induce a permanent cerebellar syndrome: phenytoin, lithium salts, antineoplastics, and heroin. In addition to ethanol and drugs, environmental agents are also a source of TOICS. In particular, the cerebellum is susceptible to metal intoxication. The recently described deposits of gadolinium in cerebellar nuclei in patients who had received multiple intravenous administrations are a matter of concern on a worldwide scale but we still lack the demonstration of clinically relevant effects upon motor, oculomotor, or cognitive function. Because cerebellar symptoms may be subtle or immersed in a complex encephalopathy with combined involvement of the peripheral nervous system, the diagnosis of TOICS is often overlooked. The life-threatening risk of edema of the posterior fossa with compression of the brainstem should be kept in mind, including in cases of posterior reversible encephalopathy syndrome, and requires posterior fossa decompression when acute hydrocephalus occurs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19 + B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells. CRS developed in 70% of patients, including 62.5% with grade 1 to 3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4, and 3.8% with grade 5. A majority of cases of grade ≥4 CRS occurred during CAR T-cell dose finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8 + central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand factor, which are biomarkers of endothelial activation, were increased during severe CRS and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR T-cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR T-cell therapy., (© 2017 by The American Society of Hematology.)

Background: Cefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood-brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions., Methods: A librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting., Results: Of the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69 years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45 mg/L (n = 21) and 13 mg/L (n = 4), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4 days, and resolution occurred a median of 2 days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis., Conclusions: Cefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.

Objective: To investigate the clinical effect and safety of electroencephalographic biofeedback therapy in improving memory disorders in patientsin the recovery stage of acute severe toxic encephalopathy. Methods: A total of 52 patients in the recovery stage of acute severe toxic encephalopathy who were hospitalized in our hospital from March 2013 to December 2016 were enrolled and randomly divided into observation group with 27 patients and control group with 25 patients. Both groups were given the drugs to promote the metabolism of brain cells,and the patients in the observation group were given electroencephalographic biofeedback therapy in addition. The Chinese revised version of Wechsler Memory Scale Type A was used to measure memory ability before and after each course of treatment. The treatment outcome was evaluated for both groups. Results: There were no significant differences in the scores of long-term memory,short-term memory, immediate memory, and memory quotient between the two groups before treatment( P >0.05).After the first course of treatment ended, the observation group had significant increases in the scores of forward task,backward task,association,and memory quotient( P <0.05); compared with the control group, the observation group had a significant reduction in the score of backward task( P <0.05).After the second course of treatmentended, the observation group had significant increases in the scores offorward task,backward task,memorization of pictures,reproduction,association,comprehension,and memory quotient,and the control group had significant increases in the scores of reproduction,association,comprehension,and memory quotient( P <0.05); compared with the control group, the observation group had significant increases in the scores of forward task,backward task,memorization of pictures, reproduction, association, comprehension, and memory quotient( P <0.05).Two patients experiencedchest distress, palpitation, and dysphoria during treatment, which did not affect the treatment. Conclusion: Electroencephalographic biofeedback therapy has a certain effect in the treatment of memory disorders in patients with acute severe toxic encephalopathy.

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

Magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery is proposed as a neuroprotective strategy against neurological alterations such as cerebral palsy in newborns. However, long-term beneficial or adverse effects of MgSO4 and sex-specific sensitivity remain to be investigated. We conducted behavioral and neurochemical studies of MgSO4 effects in males and females, from the perinatal period to adolescence in a mouse model of cerebral neonatal lesion. The lesion was produced in 5-day-old (P5) pups by ibotenate intracortical injection. MgSO4 (600 mg/kg, i.p.) prior to ibotenate prevented lesion-induced sensorimotor alterations in both sexes at P6 and P7. The lesion increased glutamate level at P10 in the prefrontal cortex, which was prevented by MgSO4 in males. In neonatally lesioned adolescent mice, males exhibited more sequelae than females in motor and cognitive functions. In the perirhinal cortex of adolescent mice, the neonatal lesion induced an increase in vesicular glutamate transporter 1 density in males only, which was negatively correlated with cognitive scores. Long-term sequelae were prevented by neonatal MgSO4 administration. MgSO4 never induced short- or long-term deleterious effect on its own. These results also strongly suggest that sex-specific neuroprotection should be foreseen in preterm infants., (© 2017 American Association of Neuropathologists, Inc. All rights reserved.)

Understanding the relationship between the molecular mechanisms underlying neurotoxicity of high-dose methamphetamine (METH) and related clinical manifestations is imperative for providing more effective treatments for human METH users. This article provides an overview of clinical manifestations of METH neurotoxicity to the central nervous system and neurobiology underlying the consequences of administration of neurotoxic METH doses, and discusses implications of METH neurotoxicity for treatment of human abusers of the drug., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Mercury vapor is highly toxic to the human body. The present study aimed to investigate the occurrence of neuropsychological dysfunction in former workers of fluorescent lamps factories that were exposed to mercury vapor (years after cessation of exposure), diagnosed with chronic mercurialism, and to investigate the effects of such exposure on the Autonomic Nervous System (ANS) using the non-invasive method of dynamic pupillometry. The exposed group and a control group matched by age and educational level were evaluated by the Beck Depression Inventory and with the computerized neuropsychological battery CANTABeclipse - subtests of working memory (Spatial Span), spatial memory (Spatial Recognition Memory), visual memory (Pattern Recognition Memory) and action planning (Stockings of Cambridge). The ANS was assessed by dynamic pupillometry, which provides information on the operation on both the sympathetic and parasympathetic functions. Depression scores were significantly higher among the former workers when compared with the control group. The exposed group also showed significantly worse performance in most of the cognitive functions assessed. In the dynamic pupillometry test, former workers showed significantly lower response than the control group in the sympathetic response parameter (time of 75% of pupillary recovery at 10cd/m 2 luminance). Our study found indications that are suggestive of cognitive deficits and losses in sympathetic autonomic activity among patients occupationally exposed to mercury vapor., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The mammalian target of rapamycin (mTOR) is a kinase involved in a variety of physiological and pathological functions. However, the exact role of mTOR in excitotoxicity is poorly understood. Here, we investigated the effects of mTOR inhibition with rapamycin against neurodegeneration, and motor impairment, as well as inflammatory profile caused by an excitotoxic stimulus., Methods: A single and unilateral striatal injection of quinolinic acid (QA) was used to induce excitotoxicity in mice. Rapamycin (250 nL of 0.2, 2, or 20 μM; intrastriatal route) was administered 15 min before QA injection. Forty-eight hours after QA administration, rotarod test was performed to evaluate motor coordination and balance. Fluoro-Jade C, Iba-1, and GFAP staining were used to evaluate neuronal cell death, microglia morphology, and astrocytes density, respectively, at this time point. Levels of cytokines and neurotrophic factors were measured by ELISA and Cytometric Bead Array 8 h after QA injection. Striatal synaptosomes were used to evaluate the release of glutamate., Results: We first demonstrated that rapamycin prevented the motor impairment induced by QA. Moreover, mTOR inhibition also reduced the neurodegeneration and the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α induced by excitotoxic stimulus. The lowest dose of rapamycin also increased the production of IL-10 and prevented the reduction of astrocyte density induced by QA. By using an in vitro approach, we demonstrated that rapamycin differently alters the release of glutamate from striatal synaptosomes induced by QA, reducing or enhancing the release of this neurotransmitter at low or high concentrations, respectively., Conclusion: Taken together, these data demonstrated a protective effect of rapamycin against an excitotoxic stimulus. Therefore, this study provides new evidence of the detrimental role of mTOR in neurodegeneration, which might represent an important target for the treatment of neurodegenerative diseases.

3-acetylpyridine (3-AP) is a metabolic antagonist used in research to decrease levels of nicotinamide (niacinamide) in laboratory animals. The administration of 3-AP followed by nicotinamide to rats leads to the selective destruction of neurons in the medial inferior olive, resulting in a loss of climbing fibers innervating cerebellar Purkinje cells and a consequent ataxia manifest by alterations in both balance and gait. Although 3-AP has also been administered to mice to destroy neurons in the inferior olive, there are limited studies quantifying the consequent effects on balance, and no studies on gait. Further, the relationship between 3-AP-induced lesions of the inferior olive and behavior has not been elucidated. Because 3-AP continues to be used for experiments involving mice, this study characterized the effects of this toxin on both balance and gait, and on the neuronal integrity of several brain regions involved in motor coordination. Results indicate that C57BL/6 mice are less sensitive to the neurotoxic effects of 3-AP than rats, and a dose more than 6.5 times that used for rats produces deficits in both balance and gait comparable to those in rats. This dose led to a significant (p<0.05) loss of NeuN(+) neurons in several subregions of the inferior olive including the rostral medial nucleus, dorsomedial cell column, ventrolateral protrusion, and cap of Kooy. Further, the number of NeuN(+) neurons in these subregions, with the exception of the dorsomedial cell column, was significantly (p<0.05) related to rotorod performance, implicating their involvement in this behavior., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Neuropsychiatric disorders caused by toxic substances pose a great diagnostic challenge due to the large variety of changes caused in the central and peripheral nervous system. The pathogenetic mechanisms at work are multifaceted and partly not solved. In human drug abusers (cannabis, opiates, cocaine, amphetamines, methamphetamine and "designer drugs"), a broad spectrum of central nervous system alterations are observed including infarction, intracerebral and subarachnoidal hemorrhage, hypoxic-ischemic leukoencephalopathy, infections, neuronal loss, specific astroglial and microglial reaction patterns, and vascular changes, including the endothelial cell as well as the basal lamina., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: HIV-associated neurocognitive disorders (HAND) continue to be a common morbidity associated with chronic HIV infection. It has been shown that HIV proteins (e.g., gp120) released from infected microglial/macrophage cells can cause neuronal damage by triggering inflammation and oxidative stress, activating aberrant kinase pathways, and by disrupting mitochondrial function and biogenesis. Previous studies have shown that FK506, an immunophilin ligand that modulates inflammation and mitochondrial function and inhibits calcineurin, is capable of rescuing the neurodegenerative pathology in models of Parkinson's disease, Alzheimer's disease, and Huntington's disease. In this context, the main objective of this study was to evaluate if FK506 could rescue the neuronal degeneration and mitochondrial alterations in a transgenic (tg) animal model of HIV1-gp120 neurotoxicity., Methods: GFAP-gp120 tg mice were treated with FK506 and analyzed for neuropathology, behavior, mitochondrial markers, and calcium flux by two-photon microscopy., Results: We found that FK506 reduced the neuronal cell loss and neuro-inflammation in the gp120 tg mice. Moreover, while vehicle-treated gp120 tg mice displayed damaged mitochondria and increased neuro-inflammatory markers, FK506 rescued the morphological mitochondrial alterations and neuro-inflammation while increasing levels of optic atrophy 1 and mitofusin 1. By two-photon microscopy, calcium levels were not affected in the gp120 tg mice and no effects of FK506 were detected. However, at a functional level, FK506 ameliorated the gp120 tg mice hyperactivity in the open field., Conclusions: Together, these results suggest that FK506 might be potentially neuroprotective in patients with HAND by mitigating inflammation and mitochondrial alterations.

One attractive pharmacological strategy for Alzheimer's disease (AD) is to design small peptides to interact with amyloid-β (Aβ) protein reducing its aggregation and toxicity. Starting from clinical observations indicating that patients coding a mutated Aβ variant (AβA2V) in the heterozygous state do not develop AD, we developed AβA2V synthetic peptides, as well as a small peptide homologous to residues 1-6. These hindered the amyloidogenesis of Aβ and its neurotoxicity in vitro, suggesting a basis for the design of a new small peptide in D-isomeric form, linked to the arginine-rich TAT sequence [Aβ1-6A2V-TAT(D)], to allow translocation across biological membranes and the blood-brain barrier. Aβ1-6A2V-TAT(D) was resistant to protease degradation, stable in serum and specifically able to interfere with Aβ aggregation in vitro, reducing the appearance of toxic soluble species and protecting transgenic C. elegans from toxicity related to the muscular expression of human Aβ. These observations offer a proof of concept for future pharmacological studies in mouse models of AD, providing a foundation for the design of AβA2V-based peptidomimetic molecules for therapeutic purposes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Trimethyltin (TMT) toxicity causes histopathological damage in the hippocampus and induces seizure behaviors in mice. The lesions and symptoms recover spontaneously over time; however, little is known about the precise mechanisms underlying this recovery from TMT toxicity. We investigated changes in the brain-derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling pathways in the mouse hippocampus following TMT toxicity. Mice (7 weeks old, C57BL/6) administered TMT (2.6 mg/kg intraperitoneally) showed acute and severe neurodegeneration with increased TUNEL-positive cells in the dentate gyrus (DG) of the hippocampus. The mRNA and protein levels of BDNF in the hippocampus were elevated by TMT treatment. Immunohistochemical analysis showed that TMT treatment markedly increased phosphorylated ERK1/2 expression in the mouse hippocampus 1-4 days after TMT treatment, although the intensity of ERK immunoreactivity in mossy fiber decreased at 1-8 days post-treatment. In addition, ERK-immunopositive cells were localized predominantly in doublecortin-positive immature progenitor neurons in the DG. In primary cultured immature hippocampal neurons (4 days in vitro), BDNF treatment alleviated TMT-induced neurotoxicity, via activation of the ERK signaling pathway. Thus, we suggest that BDNF/ERK signaling pathways may be associated with cell differentiation and survival of immature progenitor neurons, and will eventually lead to spontaneous recovery in TMT-induced hippocampal neurodegeneration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The present study is an unsubstantiated qualitative assessment of the abused drugs-tramadol and clonazepam. The aim of this study is to evaluate whether the effects of tramadol, clonazepam, and their combination on mitochondrial electron transport chain (ETC) complexes were influential at therapeutic or at progressively increasing doses. The study comprised of a total of 70 healthy male rats, aged 3 months. According to the drug intake regimen, animals were divided into seven groups: control, tramadol therapeutic, clonazepam therapeutic, combination therapeutic, tramadol abuse, clonazepam abuse, and combination abuse group. At the end of the experiment, brain mitochondrial ETC complexes (I, II, III, and IV) were evaluated. Histopathological examinations were also performed on brain tissues. The results showed that groups that received tramadol (therapeutic and abuse) suffered from weight loss. Tramadol abuse group and combination abuse group showed significant decrease in the activities of I, III, and IV complexes but not in the activity of complex II. In conclusion, tramadol but not clonazepam has been found to partially inhibit the activities of respiratory chain complexes I, III, and IV but not the activity of complex II and such inhibition occurred only at doses that exceeded the maximum recommended adult human daily therapeutic doses. This result explains the clinical and histopathological effects of tramadol, such as seizures and red neurons (marker for apoptosis), respectively., (© The Author(s) 2012.)

The prevalence of drug-associated toxic encephalopathy is unknown, but it is an uncommon condition. Toxic leukoencephalopathy was described associated with heroin consumption, it has been less commonly described with the use of cocaine and there are no reports of its association with consumption pasta base of cocaine (PBC). We report two females aged 31 years and a male aged 19 years, consumers of PBC who developed a fatal toxic leukoencephalopathy. They initiated their disease with severe and persistent headache, sequential focal neurologic deficits and a progressive impairment of consciousness that culminated with their death. Laboratory parameters such as blood count, cerebrospinal fluid analyses or infectious biological indices were normal. MRI showed multifocal lesions in brain white matter of both hemispheres confirming the leukoencephalopathy. There was no response to the use of methylprednisolone.