RESUMEN
Synthetic deer antler peptides (TSKYR, TSK, and YR) stimulate the proliferation of human chondrocytes and osteoblasts and increase the chondrocyte content of collagen and glycosamino-glycan in vitro. This study investigated the peptide mixture's pain relief and chondroprotective effect in a rat model of collagenase-induced osteoarthritis. Thirty-six adult male Sprague-Dawley rats were divided into three groups: control (saline), positive control (hyaluronic acid), and ex-perimental (peptides). Intra-articular collagenase injections were administered on days 1 and 4 to induce osteoarthritis in the left knees of the rats. Two injections of saline, hyaluronic acid, or the peptides were injected into the same knees of each corresponding group at the beginning of week one and two, respectively. Joint swelling, arthritic pain, and histopathological changes were evaluated. Injection of the peptides significantly reduced arthritic pain compared to the control group, as evidenced by the closer-to-normal weight-bearing and paw withdrawal threshold test results. Histological analyses showed reduced cartilage matrix loss and improved total cartilage degeneration score in the experimental versus the control group. Our findings suggest that intra-articular injection of synthetic deer antler peptides is a promising treatment for osteoarthritis.
Asunto(s)
Cuernos de Venado , Ciervos , Modelos Animales de Enfermedad , Osteoartritis de la Rodilla , Péptidos , Ratas Sprague-Dawley , Animales , Inyecciones Intraarticulares , Cuernos de Venado/química , Osteoartritis de la Rodilla/tratamiento farmacológico , Osteoartritis de la Rodilla/patología , Osteoartritis de la Rodilla/inducido químicamente , Masculino , Ratas , Péptidos/administración & dosificación , Péptidos/farmacología , Péptidos/uso terapéutico , Ácido Hialurónico/administración & dosificación , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Cartílago Articular/metabolismo , ColagenasasRESUMEN
Cerebrospinal fluid (CSF) and its drainage are crucial in clearing metabolic waste and maintaining the microenvironment of the central nervous system for proper functioning. Normal-pressure hydrocephalus (NPH) is a serious neurological disorder of the elderly with obstruction of CSF flow outside the cerebral ventricles, causing ventriculomegaly. The stasis of CSF in NPH compromises brain functioning. Although treatable, often with shunt implantation for drainage, the outcome depends highly on early diagnosis, which, however, is challenging. The initial symptoms of NPH are hard to be aware of and the complete symptoms overlap with those of other neurological diseases. Ventriculomegaly is not specific to NPH as well. The lack of knowledge on the initial stages in its development and throughout its progression further deters early diagnosis. Thus, we are in dire need for an appropriate animal model for researches into a more thorough understanding of its development and pathophysiology so that we can enhance the diagnosis and therapeutic strategies to improve the prognosis of NPH following treatment. With this, we review the few currently available experimental rodent NPH models for these animals are smaller in sizes, easier in maintenance, and having a rapid life cycle. Among these, a parietal convexity subarachnoid space kaolin injection adult rat model appears promising as it shows a slow onset of ventriculomegaly in association with cognitive and motor disabilities resembling the elderly NPH in humans.
RESUMEN
BACKGROUND: Hydrocephalus is characterized by abnormal accumulation of cerebrospinal fluid in the cerebral ventricles and causes motor impairments. The mechanisms underlying the motor changes remain elusive. Enlargement of ventricles compresses the striatum of the basal ganglia, a group of nuclei involved in the subcortical motor circuit. Here, we used a kaolin-injection juvenile rat model to explore the effects of acute and chronic hydrocephalus, 1 and 5 weeks post-treatment, respectively on the three major neurotransmission pathways (glutamatergic, dopaminergic and cholinergic) in the striatum. METHODS: Rats were evaluated for motor impairments. Expressions of presynaptic and postsynaptic protein markers related to the glutamatergic, dopaminergic, and cholinergic connections in the striatum were evaluated. Combined intracellular dye injection and substance P immunohistochemistry were used to distinguish between direct and indirect pathway striatal medium spiny neurons (d and i-MSNs) for the analysis of their dendritic spine density changes. RESULTS: Hydrocephalic rats showed compromised open-field gait behavior. However, male but not female rats displayed stereotypic movements and compromised rotarod performance. Morphologically, the increase in lateral ventricle sizes was greater in the chronic than acute hydrocephalus conditions. Biochemically, hydrocephalic rats had significantly decreased striatal levels of synaptophysin, vesicular glutamate transporter 1, and glutamatergic postsynaptic density protein 95, suggesting a reduction of corticostriatal excitation. The expression of GluR2/3 was also reduced suggesting glutamate receptor compositional changes. The densities of dendritic spines, morphological correlates of excitatory synaptic foci, on both d and i-MSNs were also reduced. Hydrocephalus altered type 1 (DR1) and 2 (DR2) dopamine receptor expressions without affecting tyrosine hydroxylase level. DR1 was decreased in acute and chronic hydrocephalus, while DR2 only started to decrease later during chronic hydrocephalus. Since dopamine excites d-MSNs through DR1 and inhibits i-MSNs via DR2, our findings suggest that hydrocephalus downregulated the direct basal ganglia neural pathway persistently and disinhibited the indirect pathway late during chronic hydrocephalus. Hydrocephalus also persistently reduced the striatal choline acetyltransferase level, suggesting a reduction of cholinergic modulation. CONCLUSIONS: Hydrocephalus altered striatal glutamatergic, dopaminergic, and cholinergic neurotransmission pathways and tipped the balance between the direct and indirect basal ganglia circuits, which could have contributed to the motor impairments in hydrocephalus.
Asunto(s)
Dopamina , Hidrocefalia , Ratas , Masculino , Animales , Dopamina/fisiología , Caolín/toxicidad , Transmisión Sináptica , Hidrocefalia/inducido químicamente , ColinérgicosRESUMEN
BACKGROUND/AIM: Gentamicin has been widely prescribed since the last two decades despite its ototoxicity and nephrotoxicity. Bisdemethoxycurcumin (BDMC) is an affordable and safe curcuminoid with medicinal properties. We aimed to understand the effects of BDMC on the gentamicin-induced hair cell damage in mouse cochlear UB/OC-2 cells, in order to elucidate the therapeutic potential of BDMC against gentamicin-induced ototoxicity. MATERIALS AND METHODS: We quantified the cell membrane potential and examined the regulators and cascade proteins in the intrinsic pathway of hair cell apoptosis. Mouse cochlear UB/OC-2 cells were treated with BDMC before exposure to gentamicin. The effects of BDMC on hair cell viability, mitochondrial function, and apoptosis-related proteins were examined by flow cytometry, western blot, and fluorescent staining. RESULTS: Our results revealed that BDMC reversed gentamicin-mediated cycle arrest at the G2/M phase, stabilizing the mitochondrial membrane potential, decreasing cleaved caspase proteins, and successfully reversing hair cell apoptosis. CONCLUSION: BDMC is a potential agent for reducing gentamicin-induced ototoxicity.
Asunto(s)
Gentamicinas , Ototoxicidad , Animales , Apoptosis , Diarilheptanoides/farmacología , Gentamicinas/toxicidad , Ratones , Ototoxicidad/tratamiento farmacológico , Ototoxicidad/etiología , Ototoxicidad/prevención & controlRESUMEN
Gentamicin is an important aminoglycoside antibiotic used in the treatment of gramnegative bacterial infections, but nephrotoxicity and ototoxicity reduce its utility. The autophagy pathway is involved in damage of auditory hair cells. With the aim of developing new strategies for attenuating gentamicin ototoxicity, the present study investigated the otoprotective mechanism of 2,3,4',5tetrahydroxystilbene2OßD-glucoside (THSG) in vitro using the mouse cochlear cell line UB/OC2. MTT assay demonstrated that gentamicin reduced UB/OC2 cell viability and western blotting showed that gentamicin upregulated autophagyrelated proteins, such as Beclin, autophagy related 5 and LC3II. THSG significantly attenuated gentamicininduced cytotoxicity, clearly reduced LDH release observed by LDH assay and decreased the expression of autophagyrelated proteins. Reversetranscriptionquantitative (RTq) PCR and western blotting showed that THSG against gentamicininduced autophagy via suppressing the expression of Sesn2, at both the mRNA and protein level and a possible involvement of AMPactivated protein kinase (AMPK)/mTOR signaling response. Collectively, the present study demonstrated that THSG decreased gentamicininduced ototoxicity in UB/OC2 cochlear cells via the autophagic signaling in regulating Sesn2/AMPK/mTOR pathway. These results suggested that THSG might be a new therapeutic agent with the potential to attenuate gentamicin ototoxicity.
Asunto(s)
Ototoxicidad , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Autofagia , Gentamicinas/toxicidad , Glucósidos , Ratones , Ototoxicidad/tratamiento farmacológico , Ototoxicidad/etiología , Estilbenos , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
PURPOSE: Tzu Chi University's anatomy curriculum incorporates interaction with donors' families and regards body donors as silent teachers and altruistic role models. In this silent mentor program (SMP), students learn about their donor's life before dissection to better appreciate the selfless donation. This study explores the influence of the program on students' humanistic literacy based on student letters to silent mentors, which students wrote near the end of the program and laid by the silent mentor during the coffining ceremony. METHOD: The study included 125 letters from third-year medical students who took the gross anatomy curriculum in academic years 2015, 2016, and 2017. With student consent, the program collated and published the letters in the open-access SMP yearbook. Using thematic analysis, the authors manually analyzed the letters in their original Mandarin, with the names of students made anonymous to ensure the authors were blind to students' identity throughout the study. RESULTS: The analysis identified 3 themes and 11 subthemes. Theme 1, my silent mentor, included 3 subthemes: life characteristics, altruistic attitude, and expectation of offering body. Theme 2, connection to silent mentor and family, included 4 subthemes: intersubjective bonding, emotive first encounter, spiritual communication, and encouragement from silent mentor. Theme 3, reflection and transformation, included 4 subthemes: reflection on life and death, professional self-expectation, inner transformation, and feedback action. CONCLUSIONS: The findings suggest that interactions with donors' families increased students' appreciation of the donation and enhanced students' humanistic literacy. Further, the letters seem to indicate that the SMP inspired students to develop a grateful, respectful, and empathic attitude toward life and their career. Thus, by implementing similar programs, gross anatomy curricula could go beyond the acquisition of structural knowledge to the cultivation of medical students' humanistic literacy.
Asunto(s)
Anatomía , Educación de Pregrado en Medicina , Estudiantes de Medicina , Anatomía/educación , Curriculum , Humanismo , Humanos , Mentores , Donantes de TejidosRESUMEN
BACKGROUND: Taxifolin is a flavanonol with efficacious cytoprotective properties, such as anti-inflammatory, antioxidant, anticancer, hepatoprotective, and nephroprotective effects. However, the potential protective effects of taxifolin against gentamicin-induced ototoxicity have not been confirmed. In this study, the possible mechanisms underlying the effects of taxifolin on gentamicin-induced death of UB/OC-2 cochlear cells were investigated. METHODS: Mouse cochlear UB/OC-2 cells with or without taxifolin pretreatment were exposed to gentamicin, and the effects on cytotoxicity, reactive oxygen species (ROS) production, mitochondrial permeability transition, and apoptotic marker expression were examined using biochemical techniques, flow cytometry, western blotting, and fluorescent staining. RESULTS: Little or no apparent effect of taxifolin on cell viability was observed at concentrations less than 40 µM. Further investigations showed that gentamicin significantly inhibited cell viability in a concentration-dependent manner. Pretreatment with taxifolin attenuated gentamicin-induced lactate dehydrogenase release, as well as cellular cytotoxicity. In addition, taxifolin significantly prevented gentamicin-induced cell damage by decreasing ROS production, stabilizing mitochondrial membrane potential, and downregulating the mitochondrial pathway of apoptosis. CONCLUSION: In summary, pretreatment with taxifolin is effective for mitigating gentamicin-induced apoptotic cell death mediated by the mitochondrial pathway. Our data suggest that taxifolin provides a new approach to combat gentamicin-induced ototoxicity.
Asunto(s)
Ototoxicidad , Animales , Apoptosis , Regulación hacia Abajo , Gentamicinas/toxicidad , Ratones , Quercetina/análogos & derivados , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and dementia, could be a consequence of the abnormalities of cortical milieu, such as oxidative stress, inflammation, and/or accompanied with the aggregation of ß-amyloid. The majority of AD patients are sporadic, late-onset AD, which predominantly occurs over 65 years of age. Our results revealed that the ferrous amyloid buthionine (FAB)-infused sporadic AD-like model showed deficits in spatial learning and memory and with apparent loss of choline acetyltransferase (ChAT) expression in medial septal (MS) nucleus. In hippocampal CA1 region, the loss of pyramidal neurons was accompanied with cholinergic fiber loss and neuroinflammatory responses including glial reaction and enhanced expression of inducible nitric oxide synthase (iNOS). Surviving hippocampal CA1 pyramidal neurons showed the reduction of dendritic spines as well. Astaxanthin (ATX), a potent antioxidant, reported to improve the outcome of oxidative-stress-related diseases. The ATX treatment in FAB-infused rats decreased neuroinflammation and restored the ChAT + fibers in hippocampal CA1 region and the ChAT expression in MS nucleus. It also partly recovered the spine loss on hippocampal CA1 pyramidal neurons and ameliorated the behavioral deficits in AD-like rats. From these data, we believed that the ATX can be a potential option for slowing the progression of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Región CA1 Hipocampal/efectos de los fármacos , Neuronas Colinérgicas/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Región CA1 Hipocampal/metabolismo , Neuronas Colinérgicas/metabolismo , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Masculino , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Resultado del Tratamiento , Xantófilas/farmacología , Xantófilas/uso terapéuticoRESUMEN
PURPOSE: The main tendon of the extensor hallucis longus (EHL) muscle attaches to the dorsal aspect of the distal phalanx of the great toe. One or multiple accessory tendons of the EHL have been reported in several ethnic/regional groups, except Taiwan. This study aimed to investigate the incidence, length, and insertion of the accessory tendon of the EHL in Taiwanese people. METHODS: Anatomical dissection was performed on 48 feet of 24 formalin-embalmed cadavers. The occurrence and morphological characteristics of the accessory tendon of the EHL were recorded and analyzed. RESULTS: The accessory tendon of the EHL was found in 97.92% (47/48) of the legs that were dissected. In one male cadaver, an independent muscle belly was identified in each leg, whereas all the other accessory tendons originated from the main tendon of the EHL. In this study, the insertion of the accessory tendon were classified into four patterns. The most common insertion sites were the first metatarsophalangeal (MTP) joint capsule and proximal phalanx of the great toe. The length of the accessory tendons did not correlate with age or with sex when the two tendons with independent muscle belly were excluded. CONCLUSIONS: The accessory tendon of the EHL appears to be a regular feature in Taiwanese people. Most accessory tendons of the EHL (85.7%) attached on the first MTP joint capsule may play a role in the prevention of capsular impingement during great toe extension.
Asunto(s)
Variación Anatómica , Hallux/anomalías , Músculo Esquelético/anomalías , Tendones/anomalías , Factores de Edad , Anciano , Anciano de 80 o más Años , Cadáver , Disección , Femenino , Humanos , Cápsula Articular/anomalías , Masculino , Articulación Metatarsofalángica/anomalías , Persona de Mediana Edad , Factores Sexuales , TaiwánRESUMEN
Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4',5-Tetrahydroxystilbene-2-O-ß-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/efectos de los fármacos , Gentamicinas/efectos adversos , Glucósidos/farmacología , Mitocondrias/efectos de los fármacos , Ototoxicidad/prevención & control , Estilbenos/farmacología , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Fallopia multiflora/química , Fallopia multiflora/metabolismo , Gentamicinas/farmacología , Gentamicinas/toxicidad , L-Lactato Deshidrogenasa/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/metabolismo , Ototoxicidad/complicaciones , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) and the outcome of lumboperitoneal shunt treatment remains to be systematically explored. Here, we aim to evaluate whether the severity of dopaminergic degeneration and white matter small vessel disease could be predictors of outcome for iNPH patients subjected to lumboperitoneal shunt treatment. This is a single center retrospective study with 39 patients with probable iNPH undergoing programmable surgical lumboperitoneal shunt from June 2016 to March 2018 at Hualien Tzu Chi Hospital. In all patients, dopaminergic degeneration was determined with 99mTc- TRODAT-1 SPECT scan, while white matter small vessel disease (Fazekas scale) was assessed with Brain MRI. The iNPH grading scale (iNPHGS) score and Karnofsky Performance Score (KPS) pre- and post-operation (6-month follow-up) were available for all patients. Linear regression was used to correlate the severities of dopaminergic degeneration and small vessel disease with lumboperitoneal shunt treatment outcomes. Their iNPHGS score improved significantly after surgery (pre-operatively, 7.8 ± 2.6; post-operatively, 5.7 ± 2.6 (26.9% improvement) (p < 0.05)). Moreover, the KPS was also improved significantly after surgery, by a mean of 24.6% from the baseline score (p < 0.05). A significant correlation was observed between the severity of dopaminergic degeneration and a poorer improvement of iNPHGS score (p = 0.03). However, improvement of the iNPHGS score was not correlated with white matter small vessel disease. Dopaminergic degeneration comorbidity neutralized the degree of improvement after surgery. Although white matter small vessel disease was correlated with iNPH incidence, it may not be a prognostic factor for shunt operation. These findings have implications for the use of dopaminergic imaging, as they might help predict the surgical outcome of patients with iNPH, while vascular mechanisms seem to be involved in iNPH pathophysiology.
RESUMEN
BACKGROUND: General anesthetics-induced changes of electrical oscillations in the basal ganglia may render the identification of the stimulation targets difficult. The authors hypothesized that while sevoflurane anesthesia entrains coherent lower frequency oscillations, it does not affect the identification of the subthalamic nucleus and clinical outcome. METHODS: A cohort of 19 patients with Parkinson's disease with comparable disability underwent placement of electrodes under either sevoflurane general anesthesia (n = 10) or local anesthesia (n = 9). Microelectrode recordings during targeting were compared for neuronal spiking characteristics and oscillatory dynamics. Clinical outcomes were compared at 5-yr follow-up. RESULTS: Under sevoflurane anesthesia, subbeta frequency oscillations predominated (general vs. local anesthesia, mean ± SD; delta: 13 ± 7.3% vs. 7.8 ± 4.8%; theta: 8.4 ± 4.1% vs. 3.9 ± 1.6%; alpha: 8.1 ± 4.1% vs. 4.8 ± 1.5%; all P < 0.001). In addition, distinct dorsolateral beta and ventromedial gamma oscillations were detected in the subthalamic nucleus solely in awake surgery (mean ± SD; dorsal vs. ventral beta band power: 20.5 ± 6.6% vs. 15.4 ± 4.3%; P < 0.001). Firing properties of subthalamic neurons did not show significant difference between groups. Clinical outcomes with regard to improvement in motor and psychiatric symptoms and adverse effects were comparable for both groups. Tract numbers of microelectrode recording, active contact coordinates, and stimulation parameters were also equivalent. CONCLUSIONS: Sevoflurane general anesthesia decreased beta-frequency oscillations by inducing coherent lower frequency oscillations, comparable to the pattern seen in the scalp electroencephalogram. Nevertheless, sevoflurane-induced changes in electrical activity patterns did not reduce electrode placement accuracy and clinical effect. These observations suggest that microelectrode-guided deep brain stimulation under sevoflurane anesthesia is a feasible clinical option.
Asunto(s)
Anestésicos por Inhalación/administración & dosificación , Estimulación Encefálica Profunda/métodos , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/terapia , Sevoflurano/administración & dosificación , Núcleo Subtalámico/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Adulto , Anciano , Anestésicos Locales/administración & dosificación , Ritmo beta/efectos de los fármacos , Ritmo beta/fisiología , Estudios de Cohortes , Electroencefalografía/efectos de los fármacos , Electroencefalografía/métodos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neuronas/fisiología , Enfermedad de Parkinson/fisiopatología , Núcleo Subtalámico/fisiología , Resultado del TratamientoRESUMEN
Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular ß-amyloid (Aß) infusion model of Alzheimer's disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aß-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aß-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/toxicidad , Dendritas/fisiología , Hipocampo/fisiología , Núcleos Talámicos Intralaminares/fisiología , Corteza Prefrontal/fisiología , Aprendizaje Espacial/fisiología , Memoria Espacial/fisiología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/administración & dosificación , Animales , Dendritas/efectos de los fármacos , Modelos Animales de Enfermedad , Estimulación Eléctrica , Hipocampo/citología , Hipocampo/efectos de los fármacos , Inyecciones Intraventriculares , Núcleos Talámicos Intralaminares/efectos de los fármacos , Masculino , Corteza Prefrontal/citología , Corteza Prefrontal/efectos de los fármacos , Ratas Wistar , Aprendizaje Espacial/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
Acute (e.g., traumatic brain injury or stroke) and chronic (e.g., dementia or Parkinson's disease dementia) neurological disorders that involve cognitive impairment and dysfunctional neural circuits always lead to a dreadful and costly experience for patients and their families. The application of deep brain stimulation for the treatment of neuropsychiatric disorders has shown great potential to modulate pathological neural circuits and trigger endogenous neurogenesis. We summarize several important clinical and translational studies that utilize deep brain stimulation to improve cognition based on the potentiation of neural plasticity and neurogenesis. In addition, we discuss the neuroanatomy and cerebral circuits implicated in such studies as well as the potential mechanisms underlying therapeutic benefits.
Asunto(s)
Disfunción Cognitiva/terapia , Estimulación Encefálica Profunda/métodos , Neurogénesis/fisiología , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/terapia , Cognición/fisiología , Disfunción Cognitiva/fisiopatología , Demencia/fisiopatología , Demencia/terapia , Humanos , Masculino , Memoria/fisiologíaRESUMEN
Trauma and tumor compressing the brain distort underlying cortical neurons. Compressed cortical neurons remodel their dendrites instantly. The effects on axons however remain unclear. Using a rat epidural bead implantation model, we studied the effects of unilateral somatosensory cortical compression on its transcallosal projection and the reversibility of the changes following decompression. Compression reduced the density, branching profuseness and boutons of the projection axons in the contralateral homotopic cortex 1week and 1month post-compression. Projection fiber density was higher 1-month than 1-week post-compression, suggesting adaptive temporal changes. Compression reduced contralateral cortical synaptophysin, vesicular glutamate transporter 1 (VGLUT1) and postsynaptic density protein-95 (PSD95) expressions in a week and the first two marker proteins further by 1month. ßIII-tubulin and kinesin light chain (KLC) expressions in the corpus callosum (CC) where transcallosal axons traveled were also decreased. Kinesin heavy chain (KHC) level in CC was temporarily increased 1week after compression. Decompression increased transcallosal axon density and branching profuseness to higher than sham while bouton density returned to sham levels. This was accompanied by restoration of synaptophysin, VGLUT1 and PSD95 expressions in the contralateral cortex of the 1-week, but not the 1-month, compression rats. Decompression restored ßIII-tubulin, but not KLC and KHC expressions in CC. However, KLC and KHC expressions in the cell bodies of the layer II/III pyramidal neurons partially recovered. Our results show cerebral compression compromised cortical axonal outputs and reduced transcallosal projection. Some of these changes did not recover in long-term decompression.
Asunto(s)
Transporte Axonal/fisiología , Cuerpo Calloso/lesiones , Cuerpo Calloso/metabolismo , Neuronas/metabolismo , Corteza Somatosensorial/lesiones , Corteza Somatosensorial/metabolismo , Animales , Cuerpo Calloso/patología , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large/metabolismo , Lateralidad Funcional , Cinesinas/metabolismo , Masculino , Vaina de Mielina/metabolismo , Vaina de Mielina/patología , Plasticidad Neuronal/fisiología , Neuronas/patología , Ratas Wistar , Corteza Somatosensorial/patología , Sinaptofisina/metabolismo , Tubulina (Proteína)/metabolismo , Proteína 1 de Transporte Vesicular de Glutamato/metabolismoRESUMEN
A number of neurological disorders such as epidural hematoma can cause compression of cerebral cortex. We here tested the hypothesis that sustained compression of primary somatosensory cortex may affect stellate neurons and thalamocortical afferent (TCA) fibers. A rat model with barrel cortex subjected to bead epidural compression was used. Golgi-Cox staining analyses showed the shrinkage of dendritic arbors and the stripping of dendritic spines of stellate neurons for at least 3 months post-lesion. Anterograde tracing analyses exhibited a progressive decline of TCA fiber density in barrel field for 6 months post-lesion. Due to the abrupt decrease of TCA fiber density at 3 days after compression, we further used electron microscopy to investigate the ultrastructure of TCA fibers at this time. Some TCA fiber terminal profiles with dissolved or darkened mitochondria and fewer synaptic vesicles were distorted and broken. Furthermore, the disruption of mitochondria and myelin sheath was observed in some myelinated TCA fibers. In addition, expressions of oxidative markers 3-nitrotyrosine and 4-hydroxynonenal were elevated in barrel field post-lesion. Treatment of antioxidant ascorbic acid or apocynin was able to reverse the increase of oxidative stress and the decline of TCA fiber density, rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons post-lesion. Together, these results indicate that sustained epidural compression of primary somatosensory cortex affects the TCA fibers and the dendrites of stellate neurons for a prolonged period. In addition, oxidative stress is responsible for the reduction of TCA fiber density in barrels rather than the shrinkage of dendrites and the stripping of dendritic spines of stellate neurons.
Asunto(s)
Vías Aferentes/patología , Lesiones Encefálicas/patología , Espacio Epidural , Neuronas/patología , Corteza Somatosensorial/patología , Tálamo/patología , Acetofenonas/uso terapéutico , Aldehídos/metabolismo , Animales , Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Biotina/análogos & derivados , Biotina/farmacocinética , Lesiones Encefálicas/tratamiento farmacológico , Dendritas/patología , Dendritas/ultraestructura , Dextranos/farmacocinética , Modelos Animales de Enfermedad , Complejo IV de Transporte de Electrones/metabolismo , Espacio Epidural/fisiología , Lateralidad Funcional , Masculino , Neuronas/ultraestructura , Estrés Oxidativo/fisiología , Ratas , Corteza Somatosensorial/lesiones , Tálamo/ultraestructura , Factores de Tiempo , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
Hydrocephalus is a common neurological disorder in children characterized by abnormal dilation of cerebral ventricles as a result of the impairment of cerebrospinal fluid flow or absorption. Clinical presentation of hydrocephalus varies with chronicity and often shows cognitive dysfunction. Here we used a kaolin-induction method in rats and studied the effects of hydrocephalus on cerebral cortex and hippocampus, the two regions highly related to cognition. Hydrocephalus impaired rats' performance in Morris water maze task. Serial three-dimensional reconstruction from sections of the whole brain freshly froze in situ with skull shows that the volumes of both structures were reduced. Morphologically, pyramidal neurons of the somatosensory cortex and hippocampus appear to be distorted. Intracellular dye injection and subsequent three-dimensional reconstruction and analyses revealed that the dendritic arbors of layer III and V cortical pyramid neurons were reduced. The total dendritic length of CA1, but not CA3, pyramidal neurons was also reduced. Dendritic spine densities on both cortical and hippocampal pyramidal neurons were decreased, consistent with our concomitant findings that the expressions of both synaptophysin and postsynaptic density protein 95 were reduced. These cortical and hippocampal changes suggest reductions of excitatory connectivity, which could underlie the learning and memory deficits in hydrocephalus.
Asunto(s)
Corteza Cerebral/patología , Hipocampo/patología , Hidrocefalia/complicaciones , Hidrocefalia/patología , Trastornos de la Memoria/etiología , Aprendizaje Espacial/fisiología , Animales , Antidiarreicos/toxicidad , Espinas Dendríticas/patología , Espinas Dendríticas/ultraestructura , Modelos Animales de Enfermedad , Homólogo 4 de la Proteína Discs Large/metabolismo , Hidrocefalia/inducido químicamente , Caolín/toxicidad , Aprendizaje por Laberinto , Red Nerviosa/patología , Neuronas/patología , Neuronas/ultraestructura , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
We previously reported that perineuronal astrocytic and microglial reactions are drastically upregulated in the facial nucleus after facial axotomy at the brain stem surface or the stylomastoid foramen. Furthermore, periaxonal astrocytic and microglial reactions develop retrogradely in the central facial tract which contains proximal facial axons in the brain stem. Because reconnection of interrupted peripheral nerve by microsurgical suture is a common clinical practice, the aim of this study was to investigate the spatiotemporal patterns of glial reactions in the central facial tract and the facial nucleus after facial neurorrhaphy. Here, we show immunofluorescent and immunohistochemical evidence that facial neurorrhaphy at the stylomastoid foramen largely prevented axotomy-induced astrocytic and microglial activation in the central facial tract. In contrast, glial reactions in the facial nucleus were still highly elevated after facial neurorrhaphy. Microglial and astrocytic processes were observed to ensheath the facial motoneurons in the facial nucleus. Nevertheless, the transformation of ramified to amoeboid shape of microglia, occurring at 10 weeks after facial axotomy, was not seen after neurorrhaphy. We further examined the effect of N-nitro-l-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), on glial reactions after neurorrhaphy. Western blot analyses demonstrate that inhibition of nitric oxide (NO) production significantly reduced microglial but not astrocytic reaction in the facial nucleus after neurorrhaphy. Taken together, these results indicate that in contrast to the intense glial reactions in both the central facial tract and the facial nucleus after facial axotomy, glial reactions are differentially regulated in these two compartments after facial neurorrhaphy. NO is involved in the activation of microglia in the facial nucleus after facial neurorrhaphy.
Asunto(s)
Traumatismos del Nervio Facial/patología , Nervio Facial/patología , Núcleo Motor del Nervio Facial/patología , Neuroglía/patología , Animales , Nervio Facial/metabolismo , Traumatismos del Nervio Facial/metabolismo , Núcleo Motor del Nervio Facial/metabolismo , Masculino , Neuroglía/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Behavioral adaptations during motherhood are aimed at increasing reproductive success. Alterations of hormones during motherhood could trigger brain morphological changes to underlie behavioral alterations. Here we investigated whether motherhood changes a rat's sensory perception and spatial memory in conjunction with cortical neuronal structural changes. Female rats of different statuses, including virgin, pregnant, lactating, and primiparous rats were studied. Behavioral test showed that the lactating rats were most sensitive to heat, while rats with motherhood and reproduction experience outperformed virgin rats in a water maze task. By intracellular dye injection and computer-assisted 3-dimensional reconstruction, the dendritic arbors and spines of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons were revealed for closer analysis. The results showed that motherhood and reproductive experience increased dendritic spines but not arbors or the lengths of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons. In addition, lactating rats had a higher incidence of spines than pregnant or primiparous rats. The increase of dendritic spines was coupled with increased expression of the glutamatergic postsynaptic marker protein (PSD-95), especially in lactating rats. On the basis of the present results, it is concluded that motherhood enhanced rat sensory perception and spatial memory and was accompanied by increases in dendritic spines on output neurons of the somatosensory cortex and CA1 hippocampus. The effect was sustained for at least 6 weeks after the weaning of the pups.