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Oxaliplatin-induced neurotoxicity is a growing, relevant clinical problem. In this study we evaluated the efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer. Chemotherapeutic treatment consisted of oxaliplatin 85 mg/m(2) given biweekly and weekly folinic acid 500 mg/m(2) followed by a 24-h infusion of 5-FU 2000 mg/m(2) (FUFOX). One cycle consisted of six consecutive weeks of treatment followed by two weeks of rest (=Treatment B). For Treatment A carbamazepine was added in a dosage for targeted plasma levels of 4-6 mg/L. Neurotoxicity was regularly assessed using a specific scale. Moreover, an evaluation of chronic sensory symptoms and a neurologic examination including tests for vibrational sense, strength and deep tendon reflexes were added creating a peripheral neuropathy (PNP) score. The prospectively defined adequate number of patients needed to provide power for the primary outcome could not be achieved. 19 patients were assigned to Treatment A and 17 to Treatment B. At baseline, the distribution of all clinicopathologic variables was comparable between the two groups. Overall response rates were 16% and 24% and overall survival 15.1 months and 17.4 months for Treatment A and Treatment B, respectively. Between Treatment A and Treatment B there were no major differences when considering worst neurotoxicity during the study period (p=0.46). Grade 3/4 neurotoxicity occured in 4 patients with Treatment A vs. 6 patients with Treatment B. There were no major differences between both groups in each category of the PNP score. Based on the small number of patients and low statistical power of our study definite conclusions regarding efficacy and safety of carbamazepine for prevention of oxaliplatin-associated neuropathy in patients with advanced colorectal cancer cannot be drawn.

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.

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 (AlCl3), 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 AlCl3-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl3-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl3-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.

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.

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.

Neurotoxicity is a main side effect of the anticancer drug oxaliplatin. The development of a neuropathic syndrome impairs quality of life and potentially results in chemotherapy dose reductions and/or early discontinuation. In the complex pattern of molecular and morphological alterations induced by oxaliplatin in the nervous system, an important activation of glia has been preclinically evidenced. N-Palmitoylethanolamine (PEA) modulates glial cells and exerts antinociceptive effects in several animal models. In order to improve the therapeutic chances for chemotherapy-dependent neuropathy management, the role of PEA was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mg kg-1 daily, intraperitoneally). On day 21, a single administration of PEA (30 mg kg-1 i.p.) was able to reduce oxaliplatin-dependent pain induced by mechanical and thermal stimuli. The repeated treatment with PEA (30 mg kg-1 daily i.p. for 21 days, from the first oxaliplatin injection) prevented lowering of pain threshold as well as increased pain on suprathreshold stimulation. Ex vivo histological and molecular analysis of dorsal root ganglia, peripheral nerves and spinal cord highlighted neuroprotective effects and glia-activation prevention induced by PEA repeated administration. The protective effect of PEA resulted in the normalization of the electrophysiological activity of the spinal nociceptive neurons. Finally, PEA did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. The efficacy of PEA in neuropathic pain control and in preventing nervous tissue alteration candidates this endogenous compound as disease modifying agent. These characteristics, joined to the safety profile, suggest the usefulness of PEA in chemotherapy-induced neuropathy.

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.

PurposeLimited 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.MethodsSurvivors (n = 609) completed questionnaires that evaluated hearing loss, tinnitus, stress, symptoms, and QOL. Objective measures of sensation and balance were evaluated.ResultsOf 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).ConclusionsFindings suggest that CIN, hearing loss, and tinnitus are relatively common conditions in survivors who received neurotoxic CTX.Implications for cancer survivorsSurvivors 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.

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.

PurposeChemotherapy-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/m2) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment.MethodsThree 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/m2) were compared to those within the normal BMI range (< 25 kg/m2). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity.ResultsMost 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.ConclusionsOverweight 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 SurvivorsIdentifying routinely measured patient characteristics which may contribute to an individual’s CIPN risk profile could assist with informing treatment decisions.