RESUMO
Ataxias are characterized by aberrant movement patterns closely related to cerebellar dysfunction. Purkinje cell axons are the sole outputs from the cerebellar cortex, and dysfunctional activity of Purkinje cells has been associated with ataxic movements. However, the synaptic characteristics of Purkinje cells in cases of ataxia are not yet well understood. The nicotinamide antagonist 3-acethylpyridine (3-AP) selectively destroys inferior olivary nucleus neurons so it is widely used to induce cerebellar ataxia. Five days after 3-AP treatment (65mg/kg) in adult male Sprague-Dawley rats, motor incoordination was revealed through BBB and Rotarod testing. In addition, in Purkinje cells from lobules V-VII of the cerebellar vermis studied by the Golgi method, the density of dendritic spines decreased, especially the thin and mushroom types. Western blot analysis showed a decrease in AMPA and PSD-95 content with an increase of the α-catenin protein, while GAD-67 and synaptophysin were unchanged. Findings suggest a limited capacity of Purkinje cells to acquire and consolidate afferent excitatory inputs and an aberrant, rigid profile in the movement-related output patterns of Purkinje neurons that likely contributes to the motor-related impairments characteristic of cerebellar ataxias.
Assuntos
Cerebelo , Células de Purkinje , Ratos Sprague-Dawley , Animais , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Masculino , Ratos , Cerebelo/efeitos dos fármacos , Ataxia Cerebelar/induzido quimicamente , Piridinas/farmacologia , Plasticidade Neuronal/efeitos dos fármacosRESUMO
INTRODUCTION: The use of immune checkpoint inhibitors, which have an important role in the treatment of malignant tumors, is increasing. Although rarely observed, neurological immune-related adverse events associated with immune checkpoint inhibitors result in high morbidity and mortality. Small cell lung cancer is a common cause of neurological paraneoplastic syndromes. The differentiation between paraneoplastic syndromes and neurological immune-related adverse events is important in patients using immune checkpoint inhibitors. Cerebellar ataxia caused by atezolizumab is a rare immune-related adverse event. CASE REPORT: In this context, we present a 66-year-old man with small cell lung cancer who developed immune-mediated cerebellar ataxia after three cycles of atezolizumab, a programmed cell death ligand-1 inhibitor. The admission of brain and spinal gadolinium-based contrast-enhanced magnetic resonance imaging supported the preliminary diagnosis and indicated leptomeningeal involvement. However, the blood tests and a lumbar puncture did not reveal any structural, biochemical, paraneoplastic, or infectious cause. MANAGEMENT AND OUTCOME: High-dose steroid treatment resulted in an improvement in the radiological involvement, as evidenced both clinically and on follow-up whole spine magnetic resonance imaging. Therefore, the immunotherapy was discontinued. The patient was discharged on day 20 without neurological sequelae. DISCUSSION: In light of this, we present this case to emphasize the differential diagnosis of neurological immune-related adverse events originating from immune checkpoint inhibitors, which require rapid diagnosis and treatment, and clinically similar paraneoplastic syndromes and radiologically similar leptomeningeal involvement, in a case of small cell lung cancer.
Assuntos
Ataxia Cerebelar , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Idoso , Humanos , Masculino , Anticorpos Monoclonais Humanizados/efeitos adversos , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/diagnóstico , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Síndromes Paraneoplásicas/diagnóstico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
BACKGROUND: Acute cerebellar ataxia (ACA) and acute cerebellitis represent disorders characterized by a para-infectious, post-infectious, or post-vaccination cerebellar inflammation. They are relatively common neurologic disorders among children, and may follow infections, or, more rarely, vaccinations. Few cases are instead described among infants. Although the immunization with meningococcal group B (MenB) vaccine has been associated with some neurological side effects, suspected ACA has been reported only once in the literature. CASE PRESENTATION: we describe a 7-month-old female that presented ACA within 24 h from the MenB second dose vaccination. Extensive laboratory studies and magnetic resonance imaging excluded other causes. We then conducted an extended review of other vaccine related cases reported in the literature, focusing on the clinical characteristics of ACA and finding that ataxia and cerebellitis of para- or post-infectious cause are very rarely described in the first year of life. We collected 20 articles published in the last 30 years, including an amount of 1663 patients (1-24 years) with ACA. CONCLUSIONS: a very small number of suspected post-vaccinal ataxias has been described in recent years, compared to other causes, and vaccination remains an unquestionable medical need. Further research is needed to clarify the complex pathogenesis of this disorder and its eventual link with vaccinations.
Assuntos
Ataxia Cerebelar , Vacinas Meningocócicas , Feminino , Humanos , Lactente , Doença Aguda , Ataxia Cerebelar/induzido quimicamente , Imageamento por Ressonância Magnética , Vacinas Meningocócicas/efeitos adversos , Vacinação/efeitos adversosRESUMO
Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
Assuntos
Ataxia Cerebelar , Camundongos , Animais , Ataxia Cerebelar/induzido quimicamente , Células de Purkinje/fisiologia , Microglia , Fator de Necrose Tumoral alfa/farmacologia , Cerebelo , CitocinasRESUMO
BACKGROUND: Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. This study aims to investigate the therapeutic effects of melittin (MEL) on a 3-acetylpyridine-induced (3-AP) cerebellar ataxia (CA) rat model. METHODS: Initially, CA rat models were generated by 3-AP administration followed by the subcutaneous injection of MEL. The open-field test was used for the evaluation of locomotion and anxiety. Immunohistochemistry was also conducted for the autophagy markers of LC3 and Beclin1. In the next step, the morphology of the astrocyte, the cell responsible for maintaining homeostasis in the CNS, was evaluated by the Sholl analysis. RESULTS: The findings suggested that the administration of MEL in a 3-AP model of ataxia improved locomotion and anxiety (P < 0.001), decreased the expression of LC3 (P < 0.01) and Beclin1 (P < 0.05), increased astrocyte complexity (P < 0.05) and reduced astrocyte cell soma size (P < 0.001). CONCLUSIONS: Overall, the findings imply that the MEL attenuates the 3-AP-induced autophagy, causes cell death and improves motor function. As such, it could be used as a therapeutic procedure for CA due to its neuroprotective effects.
Assuntos
Ataxia Cerebelar , Meliteno , Animais , Ratos , Ataxia/metabolismo , Autofagia , Proteína Beclina-1/metabolismo , Morte Celular , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/metabolismo , Gliose/metabolismo , Meliteno/farmacologia , Células de Purkinje , Ratos Sprague-DawleyRESUMO
INTRODUCTION: The antiseizure medication phenytoin has been associated with changes in the cerebellum, cerebellar signs, and permanent cerebellar damage. We have systematically reviewed the clinical and radiological features, and their correlation. AREAS COVERED: We identified sixty case reports and case series of the effects of phenytoin on the cerebellum by searching Medline and Embase and relevant reference lists. The reports described 92 [median 1, range 1-5] cases, documented median age 28 [2.7-78] years. Eighty-one cases described one or more clinical sign of ataxia (present in 96%), dysarthria (63%), and nystagmus (70%). The neurological outcome (in 76 cases): 10 (13%) recovered by 12 months; 55 (72%) suffered residual disability; and 11 (14%) died. Median serum phenytoin concentration (48 cases) was 50 (interquartile range 31-66) mg/L; only three values were below 20 mg/L. The radiological findings included cerebellar atrophy in 41 of 61 patients (67%) with at least one scan. EXPERT OPINION: Evidence mainly comes from case reports, and is inevitably biased. Most patients with cerebellar dysfunction have phenytoin concentrations above the reference range. Clinical signs of ataxia can persist without radiological evidence of cerebellar atrophy, and cerebellar atrophy is seen without any clinical evidence of cerebellar dysfunction.
Assuntos
Ataxia Cerebelar , Doenças Cerebelares , Adulto , Ataxia/induzido quimicamente , Ataxia/tratamento farmacológico , Ataxia/patologia , Atrofia/tratamento farmacológico , Atrofia/patologia , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/patologia , Doenças Cerebelares/induzido quimicamente , Doenças Cerebelares/diagnóstico por imagem , Doenças Cerebelares/tratamento farmacológico , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Humanos , Fenitoína/efeitos adversosRESUMO
Cerebellar ataxia (CA) is a condition in which cerebellar dysfunction leads to movement disorders such as dysmetria, asynergy and dysdiadochokinesia. This study investigates the therapeutic effects of Melittin (MEL) on 3-acetylpyridine-induced (3-AP) cerebellar ataxia (CA) rat model. Initially, CA rat models were generated by 3-AP administration followed by the intraperitoneal injection of MEL. Then, motor performance and electromyography (EMG) activity were assessed. Afterwards, the pro-inflammatory cytokines were analyzed in the cerebellar tissue. Moreover, the anti-apoptotic role of MEL in CA and its relationship with the protection of Purkinje cells were explored. The findings showed that the administration of MEL in a 3-AP model of ataxia improved motor coordination (P < 0.001) and neuro-muscular activity (p < 0.05), prevented the cerebellar volume loss (P < 0.01), reduced the level of inflammatory cytokines (p < 0.05) and thwarted the degeneration of Purkinje cells against 3-AP toxicity (P < 0.001). Overall, the findings imply that the MEL attenuates the 3-AP-induced inflammatory response. As such, it could be used as a treatment option for CA due to its anti-inflammatory effects.
Assuntos
Ataxia Cerebelar , Células de Purkinje , Animais , Apoptose , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/tratamento farmacológico , Meliteno , Piridinas , RatosRESUMO
Immune checkpoint inhibitors (ICIs) have led to a revolution in cancer management, mainly due to lasting long-term durable responses in a subset of patients with metastatic solid tumours (Gettinger et al. in JCO 36(17):1675-1684, 2018). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological immune-related adverse events (irAEs) has increased (2). Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs (Johnson et al. in J Immuno Cancer 7(1):134, 2019; Wang et al. in JAMA Oncol 4(12):1721, 2018). Small-cell lung cancer (SCLC) is common cause of neurologic paraneoplastic syndrome (Sebastian et al. in J Thorac Oncol 14(11):1878-1880, 2019). Nevertheless, the distinction between neurologic iRAEs and paraneoplastic neurological syndromes (PNSs) in patients with SCLC treated by ICIs remains challenging (Williams et al. JAMA Neurol 73(8):928, 2016). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological autoimmune adverse events has increased. Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs and have yet to be fully understood. We report a case of an immune induced cerebellar ataxia in a 47 year-old small-cell neuroendocrine carcinoma patient undergoing checkpoint blockade by atezolizumab, a programmed cell death-1 ligand (PDL-1) inhibitor. After 4 cycles of immunotherapy, the patient presented with kinetic and static cerebellar syndrome leading to the diagnosis of TRIM9-Abs ICI-related cerebellar irAE. Therapeutic management was discussed in multidisciplinary meetings in the lack of therapeutic guidelines. There was no clinical improvement. Because of high morbidity and no treatment evidence, neurologic symptoms developing under ICI require early diagnosis and may indicate the need for definitive treatment discontinuation.
Assuntos
Ataxia Cerebelar , Neoplasias , Humanos , Pessoa de Meia-Idade , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/terapia , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Imunoterapia/efeitos adversosRESUMO
BACKGROUND: Alcohol intoxication produces ataxia by affecting the cerebellum, which coordinates movements. Fragile X mental retardation (FMR) protein is a complex regulator of RNA and synaptic plasticity implicated in fragile X-associated tremor/ataxia syndrome, which features ataxia and increased Fmr1 mRNA expression resulting from epigenetic dysregulation of FMRP. We recently demonstrated that acute ethanol-induced ataxia is associated with increased cerebellar Fmr1 gene expression via histone modifications in rats, but it is unknown whether similar behavioral and molecular changes occur following chronic ethanol exposure. Here, we investigated the effects of chronic ethanol exposure on ataxia and epigenetically regulated changes in Fmr1 expression in the cerebellum. METHODS: Male adult Sprague-Dawley rats were trained on the accelerating rotarod and then fed with chronic ethanol or a control Lieber-DeCarli diet while undergoing periodic behavioral testing for ataxia during ethanol exposure and withdrawal. Cerebellar tissues were analyzed for expression of the Fmr1 gene and its targets using a real-time quantitative polymerase chain reaction assay. The epigenetic regulation of Fmr1 was also investigated using a chromatin immunoprecipitation assay. RESULTS: Ataxic behavior measured by the accelerating rotarod behavioral test developed during chronic ethanol treatment and persisted at both the 8-h and 24-h withdrawal time points compared to control diet-fed rats. In addition, chronic ethanol treatment resulted in up-regulated expression of Fmr1 mRNA and increased activating epigenetic marks H3K27 acetylation and H3K4 trimethylation at 2 sites within the Fmr1 promoter. Finally, measurement of the expression of relevant FMRP mRNA targets in the cerebellum showed that chronic ethanol up-regulated cAMP response element binding (CREB) Creb1, Psd95, Grm5, and Grin2b mRNA expression without altering Grin2a, Eaa1, or histone acetyltransferases CREB binding protein (Cbp) or p300 mRNA transcripts. CONCLUSIONS: These results suggest that epigenetic regulation of Fmr1 and subsequent FMRP regulation of target mRNA transcripts constitute neuroadaptations in the cerebellum that may underlie the persistence of ataxic behavior during chronic ethanol exposure and withdrawal.
Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Ataxia Cerebelar/induzido quimicamente , Cerebelo/efeitos dos fármacos , Etanol/efeitos adversos , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Intoxicação Alcoólica/etiologia , Intoxicação Alcoólica/metabolismo , Animais , Depressores do Sistema Nervoso Central/administração & dosagem , Ataxia Cerebelar/metabolismo , Cerebelo/metabolismo , Epigênese Genética/efeitos dos fármacos , Etanol/administração & dosagem , Código das Histonas/efeitos dos fármacos , Masculino , Ratos Sprague-DawleyRESUMO
Cerebellar ataxia is a neurodegenerative disorder with no definitive treatment. Although several studies have demonstrated the neuroprotective effects of Hericium erinaceus (H.E.), its mechanisms in cerebellar ataxia remain largely unknown. Here, we investigated the neuroprotective effects of H.E. treatment in an animal model of 3-acetylpyridine (3-AP)-induced cerebellar ataxia. Animals administered 3-AP injection exhibited remarkable impairments in motor coordination and balance. There were no significant effects of 25 mg/kg H.E. on the 3-AP treatment group compared to the 3-AP saline group. Interestingly, there was also no significant difference in the 3-AP treatment group compared to the non-3-AP control, indicating a potential rescue of motor deficits. Our results revealed that 25 mg/kg H.E. normalised the neuroplasticity-related gene expression to the level of non-3-AP control. These findings were further supported by increased protein expressions of pERK1/2-pCREB-PSD95 as well as neuroprotective effects on cerebellar Purkinje cells in the 3-AP treatment group compared to the 3-AP saline group. In conclusion, our findings suggest that H.E. potentially rescued behavioural motor deficits through the neuroprotective mechanisms of ERK-CREB-PSD95 in an animal model of 3-AP-induced cerebellar ataxia.
Assuntos
Comportamento Animal/efeitos dos fármacos , Ataxia Cerebelar/tratamento farmacológico , Hericium/crescimento & desenvolvimento , Transtornos Motores/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/toxicidade , Piridinas/toxicidade , Animais , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/psicologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hericium/química , Masculino , Transtornos Motores/genética , Transtornos Motores/metabolismo , Transtornos Motores/patologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/patologia , Ratos , Ratos Sprague-DawleyRESUMO
Most cerebellar ataxias (CAs) are incurable neurological disorders, resulting in a lack of voluntary control by inflamed or damaged cerebellum. Although CA can be either directly or indirectly related to cerebellar inflammation, there is no suitable animal model of CA with neuroinflammation. In this study, we evaluated the utility of an intracerebellar injection of lipopolysaccharide (LPS) to generate an animal model of inflammatory CA. We observed that LPS administration induced the expression of pro-inflammatory molecules following activation of glial cells. In addition, the administration of LPS resulted in apoptotic Purkinje cell death and induced abnormal locomotor activities, such as impaired motor coordination and abnormal hindlimb clasping posture. Our results suggest that intracerebellar LPS administration in experimental animals may be useful for studying the inflammatory component of CA.
Assuntos
Ataxia Cerebelar/induzido quimicamente , Inflamação/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Animais , Células Cultivadas , Cerebelo/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/efeitos dos fármacos , Células de Purkinje/efeitos dos fármacosRESUMO
BACKGROUND AND AIM: Neurodegeneration has been associated with the use of combination antiretroviral therapy (cART). This study is aimed at determining if any constituent of cART can induce cerebellar limb dysmetria and spatial memory impairments. MATERIALS AND METHODS: Forty adult male Wistar rats were randomly grouped into four (nâ¯=â¯10): control (distilled water 0.5â¯mL); Tenofovir (6â¯mg/kg); Lamivudine (6â¯mg/kg) and Efavirenz (12â¯mg/kg). The following neurobehavioral studies were conducted: open field, beam walk, and Morris water maze. Immunohistochemistry of CD 68 and GFAP were used to test for neuroinflammation and neurodegeneration. RESULTS: There was marked increase in pyknotic pyramidal cells of the hippocampus and ghost Purkinje cells in the cerebellum of treatment groups. There was also a significant increase in oxidative stress in lamivudine and efavirenz groups. In addition, Lamivudine caused a significant increase of microglial and astrocytic activity (pâ¯<â¯0.001, 0.05 respectively) compared to control. The open field test showed a significant decrease (pâ¯<â¯0.0001) of the line crossing performance in the efavirenz, lamivudine and tenofovir (with means: 26.4, 4.6, 17.4 respectively) compared to control (50.6). There was also a significant decrease in the grooming (pâ¯<â¯0.05) and rearing (pâ¯<â¯0.01) in lamivudine group. Whereas, walk latency increased in efavirenz (pâ¯<â¯0.01), and lamivudine (pâ¯<â¯0.0001) compared to control. While hind limb slips significantly increased in efavirenz (pâ¯<â¯0.05) and lamivudine (pâ¯<â¯0.0001) compared with control group. Likewise, Lamivudine and Tenofovir exposed groups experienced a significant delay in the time to identify the hidden platform in compared to control (pâ¯<â¯0.05). CONCLUSION: Lamivudine altered efferent stimuli along the cerebellospinal tracts thereby causing motor impairments. The degenerating Purkinje fibers may have induced marked neurodegeneration in the hippocampus resulting in impaired spatial memory.
Assuntos
Ataxia Cerebelar/induzido quimicamente , Lamivudina/efeitos adversos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Alcinos/administração & dosagem , Alcinos/efeitos adversos , Animais , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Ciclopropanos/administração & dosagem , Ciclopropanos/efeitos adversos , Modelos Animais de Doenças , Lamivudina/administração & dosagem , Masculino , Ratos , Ratos Wistar , Tenofovir/administração & dosagem , Tenofovir/efeitos adversosRESUMO
The cerebellum is widely known as a motor structure because it regulates and controls motor learning, coordination, and balance. However, it is also critical for non-motor functions such as cognitive processing, sensory discrimination, addictive behaviors and mental disorders. The cerebellum has the highest relative abundance of neuronal nitric oxide synthase (nNos) and is sensitive to ethanol. Although it has been demonstrated that the interaction of γ-aminobutyric acid (GABA) and nitric oxide (NO) might play an important role in the regulation of ethanol-induced cerebellar ataxia, the molecular mechanisms through which ethanol regulates nNos function to elicit this behavioral effect have not been studied extensively. Here, we investigated the dose-dependent effects of acute ethanol treatment on motor impairment using the rotarod behavioral paradigm and the alterations of nNos mRNA expression in cerebellum, frontal cortex (FC), hippocampus and striatum. We also examined the link between acute ethanol-induced motor impairment and nNos by pharmacological manipulation of nNos function. We found that acute ethanol induced a dose-dependent elevation of ethanol blood levels which was associated with the impairment of motor coordination performance and decreased expression of cerebellar nNos. In contrast, acute ethanol increased nNos expression in FC but did not to change the expression for this enzyme in striatum and hippocampus. The effects of acute ethanol were attenuated by l-arginine, a precursor for NO and potentiated by 7-nitroindazole (7-NI), a selective inhibitor of nNos. Our data suggests that differential regulation of nNos mRNA expression in cerebellum and frontal cortex might be involved in acute ethanol-induced motor impairment.
Assuntos
Transtornos do Sistema Nervoso Induzidos por Álcool/metabolismo , Ataxia Cerebelar/metabolismo , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo I/metabolismo , Transtornos Psicomotores/metabolismo , Transtornos do Sistema Nervoso Induzidos por Álcool/induzido quimicamente , Animais , Arginina/farmacologia , Ataxia Cerebelar/induzido quimicamente , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Inibidores Enzimáticos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Indazóis/farmacologia , Masculino , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Transtornos Psicomotores/induzido quimicamente , Ratos Sprague-DawleyRESUMO
Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. Cell replacement therapy (CRT) has been considered as a potential treatment for neurological disorders. In this report, we investigated the neuro-restorative effects of human chorionic stem cells (HCSCs) transplantation on rat model of CA induced by 3-acetylpyridine (3-AP). In this regard, HCSCs were isolated and phenotypically determined. Next, a single injection of 3-AP was administered for ataxia induction, and bilateral HCSCs implantation was conducted 3 days after 3-AP injection, followed by expression analysis of a number of apoptotic, autophagic and inflammatory genes as well as vascular endothelial growth factor (VEGF) level, along with assessment of cerebellar neurodegeneration, motor coordination and muscle activity. The findings revealed that grafting of HCSCs in 3-AP model of ataxia decreased the expression levels of several inflammatory, autophagic and apoptotic genes and provoked the up-regulation of VEGF in the cerebellar region, prevented the degeneration of Purkinje cells caused by 3-AP toxicity and ameliorated motor coordination and muscle function. In conclusion, these data indicate in vivo efficacy of HCSCs in the reestablishment of motor skills and reversal of CA.
Assuntos
Ataxia Cerebelar/terapia , Cerebelo/patologia , Atividade Motora/fisiologia , Degeneração Neural/terapia , Transplante de Células-Tronco , Células-Tronco/metabolismo , Animais , Apoptose/fisiologia , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/metabolismo , Ataxia Cerebelar/fisiopatologia , Cerebelo/metabolismo , Cerebelo/fisiopatologia , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/fisiopatologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Piridinas , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Cerebellar ataxias comprise a group of terminal illnesses with ataxia as the main symptom. Curcumin as a yellow polyphenol was extracted from the rhizome ofCurcuma longa. Owing to its antioxidant, anti-inflammatory, anti-fibrotic and anti-tumor features, curcumin is considered as a potential therapeutic agent. AIM: In this study, we aim to investigate the neuroprotective effects of oral administration of curcumin on a rat model of cerebellar ataxia induced by neurotoxin 3-acetylpyridine. METHODS: The animals were randomly separated into three groups (control, 3-acetylpyridine, and curcumin + 3-acetylpyridine). Next, motor performance and muscle electromyography activity were assessed. Then, in the molecular part of the study, the anti-apoptotic role of curcumin in cerebellar ataxia and its relationship to protection of Purkinje cells were investigated. RESULTS: Curcumin treatment improved motor coordination and muscular activity, reduced cleaved caspase-3, and increased glutathione level in 3-AP-lesioned rats as well as total volumes of cerebellar granular and molecular layers. CONCLUSION: the present study implies that curcumin might have neuroprotective effects to counteract neurotoxicity of 3-AP-induced ataxia.
Assuntos
Atrofia/tratamento farmacológico , Ataxia Cerebelar/tratamento farmacológico , Cerebelo/efeitos dos fármacos , Curcumina/uso terapêutico , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Células de Purkinje/efeitos dos fármacos , Animais , Atrofia/induzido quimicamente , Atrofia/patologia , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/patologia , Cerebelo/patologia , Curcumina/farmacologia , Modelos Animais de Doenças , Eletromiografia , Masculino , Fármacos Neuroprotetores/farmacologia , Células de Purkinje/patologia , Piridinas , Ratos , Ratos Sprague-DawleyRESUMO
Case presentation: A 66-year-old gentleman with metastatic non-small-cell lung cancer developed a wide-based gait following treatment on a clinical trial with cytotoxic chemotherapy and an anti-PD-L1 drug. He had no other significant past medical history of note. Brain imaging, blood tests and lumbar puncture did not reveal a structural, biochemical, paraneoplastic or infective cause. The main differential diagnoses were immune-mediated toxicity or a paraneoplastic syndrome. He was started on prednisolone on the suspicion that his symptoms represented an immune-mediated toxicity. His condition improved following this and his immunotherapy treatment was discontinued. Upon steroid withdrawal, his symptoms recurred and responded to further prednisolone. Conclusions: Immune-mediated toxicities can affect any part of the nervous system and should form part of the differential diagnosis for new neurological symptoms in a patient receiving immunotherapy. Corticosteroids should be the first-line treatment of immune-mediated toxicities. Immunotherapy should be permanently discontinued following severe toxicities.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ataxia Cerebelar/induzido quimicamente , Ataxia Cerebelar/diagnóstico , Imunoterapia/efeitos adversos , Idoso , Antineoplásicos Hormonais/uso terapêutico , Diagnóstico Diferencial , Humanos , Masculino , Prednisolona/uso terapêutico , Resultado do TratamentoRESUMO
We herein report a 68-year-old man with neurologic immune-related adverse events (irAEs) who exhibited nivolumab-induced steroid-responsive progressive ataxia, tremor, and anti-thyroid antibodies. His symptoms matched abnormalities on N-isopropyl-p-(123I)-iodoamphetamine single-photon emission computed tomography (SPECT) and dopamine transporter SPECT. Based on these clinical findings, we diagnosed the patient with a condition similar to the cerebellar type of Hashimoto's encephalopathy with nivolumab-induced anti-thyroid antibodies. Neurologic irAEs can be difficult to diagnose due to their varied clinical courses and lack of specific examinations. Therefore, a comprehensive approach, including assessments of autoantibodies and functional imaging, might be important for the diagnosis of neurologic irAEs.