RESUMEN
Cancer survivors rank sensorimotor disability among the most distressing, long-term consequences of chemotherapy. Disorders in gait, balance, and skilled movements are commonly assigned to chemotoxic damage of peripheral sensory neurons without consideration of the deterministic role played by the neural circuits that translate sensory information into movement. This oversight precludes sufficient, mechanistic understanding and contributes to the absence of effective treatment for reversing chemotherapy-induced disability. We rectified this omission through the use of a combination of electrophysiology, behavior, and modeling to study the operation of a spinal sensorimotor circuit in vivo in a rat model of chronic, oxaliplatin (chemotherapy)-induced neuropathy (cOIN). Key sequential events were studied in the encoding of propriosensory information and its circuit translation into the synaptic potentials produced in motoneurons. In cOIN rats, multiple classes of propriosensory neurons expressed defective firing that reduced accurate sensory representation of muscle mechanical responses to stretch. Accuracy degraded further in the translation of propriosensory signals into synaptic potentials as a result of defective mechanisms residing inside the spinal cord. These sequential, peripheral, and central defects compounded to drive the sensorimotor circuit into a functional collapse that was consequential in predicting the significant errors in propriosensory-guided movement behaviors demonstrated here in our rat model and reported for people with cOIN. We conclude that sensorimotor disability induced by cancer treatment emerges from the joint expression of independent defects occurring in both peripheral and central elements of sensorimotor circuits.
Asunto(s)
Antineoplásicos/efectos adversos , Trastornos Neurológicos de la Marcha/inducido químicamente , Mecanorreceptores/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Animales , Femenino , Masculino , Neoplasias/tratamiento farmacológico , Propiocepción/efectos de los fármacos , Ratas Endogámicas F344RESUMEN
OBJECTIVES: The purpose of the experiment was to estimate whether intrathecal antimalarial drugs could provoke spinal block, and their comparison with lidocaine. METHODS: Rats were intrathecally administrated with antimalarial agents (primaquine, chloroquine, hydroxychloroquine and amodiaquine) and lidocaine, and neurobehavioural examinations (nociception, proprioception and motor function) were assessed; n = 8 per group. One-way and two-way analysis of variance were designed to analyse data. KEY FINDINGS: At a concentration of 20 mM, primaquine (0.46 mg/rat) exhibited the longest duration and the most potent effect of nociceptive, proprioceptive and motor blockade (P < 0.01) among five drugs, whereas the other antimalarial drugs displayed a lesser or similar potency of spinal blockade compared with lidocaine (0.29 mg/rat). In dose-dependent studies, primaquine was more potent (P < 0.01) than lidocaine for spinal block. At ED25, ED50 and ED75 equipotent doses, primaquine produced a greater duration of spinal motor, proprioceptive and nociceptive blockade when compared with lidocaine (P < 0.01). CONCLUSIONS: Primaquine, chloroquine, hydroxychloroquine and amodiaquine produced spinal blockade. Primaquine was more potent and displayed a prolonged life of local anaesthetic effect compared with lidocaine, whereas the other antimalarial drugs displayed a lesser or similar potency compared with lidocaine.
Asunto(s)
Anestesia Raquidea/métodos , Anestésicos Locales/farmacología , Antimaláricos/farmacología , Actividad Motora/efectos de los fármacos , Nocicepción/efectos de los fármacos , Primaquina/farmacología , Propiocepción/efectos de los fármacos , Aminoquinolinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Inyecciones Espinales , Lidocaína/farmacología , Masculino , Bloqueo Nervioso/métodos , Ratas Sprague-DawleyRESUMEN
Motor recovery after severe spinal cord injury (SCI) is limited due to the disruption of direct descending commands. Despite the absence of brain-derived descending inputs, sensory afferents below injury sites remain intact. Among them, proprioception acts as an important sensory source to modulate local spinal circuits and determine motor outputs. Yet, it remains unclear whether enhancing proprioceptive inputs promotes motor recovery after severe SCI. Here, we first established a viral system to selectively target lumbar proprioceptive neurons and then introduced the excitatory Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADD) virus into proprioceptors to achieve specific activation of lumbar proprioceptive neurons upon CNO administration. We demonstrated that chronic activation of lumbar proprioceptive neurons promoted the recovery of hindlimb stepping ability in a bilateral hemisection SCI mouse model. We further revealed that chemogenetic proprioceptive stimulation led to coordinated activation of proprioception-receptive spinal interneurons and facilitated transmission of supraspinal commands to lumbar motor neurons, without affecting the regrowth of proprioceptive afferents or brain-derived descending axons. Moreover, application of 4-aminopyridine-3-methanol (4-AP-MeOH) that enhances nerve conductance further improved the transmission of supraspinal inputs and motor recovery in proprioception-stimulated mice. Our study demonstrates that proprioception-based combinatorial modality may be a promising strategy to restore the motor function after severe SCI.
Asunto(s)
Aminopiridinas/administración & dosificación , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Neuronas Motoras/fisiología , Traumatismos de la Médula Espinal/terapia , Aminopiridinas/farmacología , Animales , Terapia Combinada , Dependovirus/genética , Modelos Animales de Enfermedad , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Humanos , Ratones , Neuronas Motoras/metabolismo , Conducción Nerviosa/efectos de los fármacos , Propiocepción/efectos de los fármacos , Recuperación de la Función , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.
Asunto(s)
Trastornos del Movimiento/tratamiento farmacológico , Atrofia Muscular Espinal/tratamiento farmacológico , Desempeño Psicomotor/efectos de los fármacos , Trastornos de la Sensación/tratamiento farmacológico , 4-Aminopiridina/uso terapéutico , Animales , Muerte Celular/efectos de los fármacos , Ratones , Ratones Noqueados , Neuronas Motoras/efectos de los fármacos , Trastornos del Movimiento/etiología , Trastornos del Movimiento/psicología , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/psicología , Unión Neuromuscular/efectos de los fármacos , Bloqueadores de los Canales de Potasio/uso terapéutico , Propiocepción/efectos de los fármacos , Trastornos de la Sensación/etiología , Trastornos de la Sensación/psicología , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Proteína p53 Supresora de Tumor/antagonistas & inhibidoresRESUMEN
PIEZO2 is the essential transduction channel for touch discrimination, vibration, and proprioception. Mice and humans lacking Piezo2 experience severe mechanosensory and proprioceptive deficits and fail to develop tactile allodynia. Bradykinin, a proalgesic agent released during inflammation, potentiates PIEZO2 activity. Molecules that decrease PIEZO2 function could reduce heightened touch responses during inflammation. Here, we find that the dietary fatty acid margaric acid (MA) decreases PIEZO2 function in a dose-dependent manner. Chimera analyses demonstrate that the PIEZO2 beam is a key region tuning MA-mediated channel inhibition. MA reduces neuronal action potential firing elicited by mechanical stimuli in mice and rat neurons and counteracts PIEZO2 sensitization by bradykinin. Finally, we demonstrate that this saturated fatty acid decreases PIEZO2 currents in touch neurons derived from human induced pluripotent stem cells. Our findings report on a natural product that inhibits PIEZO2 function and counteracts neuronal mechanical sensitization and reveal a key region for channel inhibition.
Asunto(s)
Ácidos Grasos/administración & dosificación , Canales Iónicos/antagonistas & inhibidores , Mecanotransducción Celular/efectos de los fármacos , Neuronas/efectos de los fármacos , Propiocepción/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Algoritmos , Animales , Células Cultivadas , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/fisiología , Canales Iónicos/genética , Canales Iónicos/metabolismo , Mecanotransducción Celular/genética , Mecanotransducción Celular/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Neuronas/fisiología , Propiocepción/genética , Propiocepción/fisiología , Ratas , Tacto/efectos de los fármacos , Tacto/fisiologíaRESUMEN
(1) Background: In dystonia, the somatosensory temporal discrimination threshold (STDT) is abnormally increased at rest and higher and longer-lasting during movement execution in comparison with healthy subjects (HS), suggesting an abnormal sensorimotor integration. These abnormalities are thought to depend on abnormal proprioceptive input coming from dystonic muscles. Since Botulinum toxin-A (BT-A) reduces proprioceptive input in the injected muscles, our study investigated the effects of BT-A on STDT tested at rest and during voluntary movement execution in patients with focal dystonia. (2) Methods: We enrolled 35 patients with focal dystonia: 14 patients with cervical dystonia (CD), 11 patients with blepharospasm (BSP), and 10 patients with focal hand dystonia (FHD); and 12 age-matched HS. STDT tested by delivering paired stimuli was measured in all subjects at rest and during index finger abductions. (3) Results: Patients with dystonia had higher STDT values at rest and during movement execution than HS. While BT-A did not modify STDT at rest, it reduced the abnormal values of STDT during movement in CD and FHD patients, but not in BSP patients. (4) Conclusions: BT-A improved abnormal sensorimotor integration in CD and FHD, most likely by decreasing the overflow of proprioceptive signaling from muscle dystonic activity to the thalamus.
Asunto(s)
Inhibidores de la Liberación de Acetilcolina/uso terapéutico , Blefaroespasmo/tratamiento farmacológico , Toxinas Botulínicas Tipo A/uso terapéutico , Encéfalo/efectos de los fármacos , Trastornos Distónicos/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Propiocepción/efectos de los fármacos , Tortícolis/tratamiento farmacológico , Inhibidores de la Liberación de Acetilcolina/efectos adversos , Adolescente , Adulto , Anciano , Fenómenos Biomecánicos , Blefaroespasmo/diagnóstico , Blefaroespasmo/fisiopatología , Toxinas Botulínicas Tipo A/efectos adversos , Encéfalo/fisiopatología , Trastornos Distónicos/diagnóstico , Trastornos Distónicos/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuperación de la Función , Factores de Tiempo , Tortícolis/diagnóstico , Tortícolis/fisiopatología , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect deriving from neurotoxic chemotherapeutic agents. The underlying nerve injury can affect proprioception causing impaired postural control, gait difficulties and a higher risk of falling. Overall, the symptoms and functional limitations negatively affect patients' independence and quality of life. RESEARCH QUESTION: Our objective was to analyze postural control in cancer patients before and after neurotoxic chemotherapy and to compare these data to healthy controls. METHODS: Participants were 35 cancer patients (PAT) and 35 healthy, one-to-one gender, age, height, and weight matched controls (HMC). Postural control of HMC was tested once, whereas PAT were tested prior to (PATpre) and three weeks after completion of neurotoxic chemotherapy (PATpost). Temporal, spatial and frequency domain measures of the center of pressure (COP) were calculated using a force plate. The following balance conditions were analyzed: bipedal stance with open (BPEO) and closed eyes (BPEC), semi-tandem (STEO, STEC) and monopedal stance (MPEO). CIPN was assessed clinically (Total Neuropathy Score) and via questionnaire. Time and group differences were determined by using Wilcoxon-signed-rank tests. Spearman correlation was applied to analyze associations between severity of CIPN and postural control. RESULTS: PATpost showed significantly increased temporal and spatial measures of the COP (pâ¯<â¯.05) - both after neurotoxic chemotherapy (PATpre-PATpost) and in comparison to HMC. Withdrawal of visual control resulted in greater temporal and spatial COP displacements in PATpost than in the comparative groups (PATpre, HMC). Correlation analyzes revealed moderate associations of COP measures with clinical CIPN measures and low to none for the questionnaires. SIGNIFICANCE: Three weeks after completion of neurotoxic chemotherapy, PATpost showed significant balance deficits compared to PATpre and HMC. Especially the deficits in the standing conditions with closed eyes may indicate an impaired proprioception. This hypothesis is supported by the finding that stronger CIPN symptoms were associated with poorer postural control. However, future studies need to take further influencing factors on postural control into account (e.g. strength) in order to generate efficacious rehabilitation measures.
Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Equilibrio Postural/efectos de los fármacos , Accidentes por Caídas , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/fisiopatología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Equilibrio Postural/fisiología , Propiocepción/efectos de los fármacos , Estudios Prospectivos , Calidad de VidaRESUMEN
The Rubber Hand Illusion (RHI) is an experimental paradigm for assessing changes in body ownership. Recent findings in the field suggest that social emotions can influence such changes and that empathic motivation in particular appears to positively predict the malleability of body representations. Since the steroid hormone, testosterone, is well known to interrupt certain forms of empathic processing, in the current study we investigated whether 0.5 mg of testosterone affected ownership indices of the RHI. Forty-nine females participated in a double-blind, placebo-controlled experiment in which the RHI was induced. Compared to placebo, testosterone had no effects on the alteration of subjective ownership over the rubber limb or on subjective sense of proprioceptive drift. However, unlike the placebo group, testosterone-treated participants did not display an objective decline in the temperature of their own (hidden) hand following induction of the illusion. These findings suggest that testosterone strengthens implicit but not explicit bodily self-representations. We propose that effective maintenance of implicit body boundaries can be regarded, conceptually, as a primary defensive state facilitating integrity of the self.
Asunto(s)
Imagen Corporal , Emociones/fisiología , Mano/fisiología , Ilusiones/efectos de los fármacos , Propiocepción/efectos de los fármacos , Testosterona/farmacología , Percepción del Tacto/efectos de los fármacos , Adolescente , Adulto , Andrógenos/farmacología , Frío , Femenino , Voluntarios Sanos , Humanos , Adulto JovenRESUMEN
Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease. OBJECTIVE: This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 µg, 10 µg, and 20 µg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response. METHODS: This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 µg, 10 µg, 20 µg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days). RESULTS: Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 µg (n = 12), 10 µg (n = 12), or 20 µg (n = 12) LSD. LSD plasma levels were undetectable for the 5 µg group and peak blood plasma levels for the 10 µg and 20 µg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment. CONCLUSIONS: Our results suggest safety and tolerability of orally administered 5 µg, 10 µg, and 20 µg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD).
Asunto(s)
Cognición/efectos de los fármacos , Alucinógenos/administración & dosificación , Alucinógenos/farmacología , Dietilamida del Ácido Lisérgico/administración & dosificación , Dietilamida del Ácido Lisérgico/farmacocinética , Propiocepción/efectos de los fármacos , Administración Oral , Anciano , Cognición/fisiología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Propiocepción/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiologíaRESUMEN
Developmental cell death plays an important role in the construction of functional neural circuits. In vertebrates, the canonical view proposes a selection of the surviving neurons through stochastic competition for target-derived neurotrophic signals, implying an equal potential for neurons to compete. Here we show an alternative cell fitness selection of neurons that is defined by a specific neuronal heterogeneity code. Proprioceptive sensory neurons that will undergo cell death and those that will survive exhibit different molecular signatures that are regulated by retinoic acid and transcription factors, and are independent of the target and neurotrophins. These molecular features are genetically encoded, representing two distinct subgroups of neurons with contrasted functional maturation states and survival outcome. Thus, in this model, a heterogeneous code of intrinsic cell fitness in neighboring neurons provides differential competitive advantage resulting in the selection of cells with higher capacity to survive and functionally integrate into neural networks.