Cholinergic system changes of falls and freezing of gait in Parkinson’s disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149240/1/ana25430_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149240/2/ana25430.pd

Development of Novel Radiotracer for Imaging High Affinity Choline Transporter and Vesicular and Acetyl Choline Transporter

13301甲第4135号博士（薬学）金沢大学博士論文本文Ful

Cholinergic system in sequelae of traumatic brain injury

Background: Traumatic brain injury (TBI) is one of the most significant causes of disability and lowered capacity. TBI cause also a considerable financial burden since the majority of patients are young at the time of injury. Though much scientific work has been conducted, the pathophysiological mechanisms behind the sequelae of TBI are still largely unknown. However, there is evidence emerging from experimental and clinical studies that the cholinergic system seems to be at least partly involved in the cognitive impairment associated with TBI. In the TBI aftermath, patients commonly experience problems with attention, initiative and processing speed, i.e. functions which are mainly regulated by the cholinergic system. Additionally, in particular there are indications that the structures containing acetylcholinecontaining neurons are commonly injured in TBI. Furthermore, there is preliminary evidence that at least some TBI patients may benefit from cholinergic medication. Aims of the study: Our aim was to utilize positron emission tomography (PET) and magnetic resonance imaging (MRI) to evaluate possible alterations in the cholinergic system after TBI. An additional goal was to clarify the association of these structural or functional changes to the patient’s response to cholinergic medication. Patients with moderate-to-severe TBI were compared to healthy controls with PET using the [11C]MP4A tracer. MP4A targets acetylcholinesterase (AChE), which is the pre- and post-synaptic acetylcholine degrading enzyme. The TBI patient group was divided into two depending on their response to rivastigmine (inhibitor of AChE) treatment. These patient groups were imaged with MP4A-PET at baseline (without medication) and after 4 weeks of rivastigmine therapy to compare differences in AChE activity. Cholinergic structures were also investigated with atlas-based MRI morphometry. It was also examined whether the atrophy rates of frontal cholinergic structures were associated with neuropsychological tests results. The subjects filled in a questionnaire to determine whether their smoking histories had any connection to the outcome of TBI. Results: The AChE activity in TBI patients was clearly lowered in cortical regions when compared to controls. Most significantly, AChE activity was reduced in parieto- and occipital-cortices. A comparison of the two TBI patient groups in the primary time point scan showed evidence of lowered AChE activity in frontal cortical structures in rivastigmine responders. However, the inhibitory effect of rivastigmine on AChE activity was similar with patient groups when scanned during drug therapy and there was no longer any significant difference between groups in their AChE activities. MRI morphometry revealed that the higher the atrophy rate in frontal cortical structures, the poorer the performance in neuropsychological tests measuring attention. Smoking history was not associated with TBI outcome. Conclusions: According to the results of this study, it appears that the cholinergic system is altered chronically after TBI. It also seems that these structural alterations and the consequential functional changes in the cholinergic system are connected to the response to cholinergic medication. Additionally, the atrophy rate of frontal cortical structures, which are mainly innervated by cholinergic neurons, appears to have correlation to neuropsychological performance concerning attention. There did not seem to be any link between smoking and TBI outcome

Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction

214 p.The selective vulnerability of the basal forebrain cholinergic system (BFCS) is responsible for most of the clinical alterations in learning and memory processes that are characteristic of the Alzheimer¿s disease (AD). The loss of cholinergic neurons and muscarinic receptors (MR) in the nucleus basalis of Meynert has been reported in AD. The endocannabinoid system is a neuromodulator of the BFCS, but there are controversial reports regarding the cannabinoid effects in learning and memory processes.The animal models of cholinergic impairment mimick the main histopathological and behavioral effects observed in patients. The MR antagonism, e.g. using scopolamine (SCOP), is used as a model of amnesia in rodents. The intraparenchymal administration of 192-IgG-saporin (SAP) in the nucleus basalis magnocellularis eliminates cholinergic neurons leading to learning and memory deficits.Then, the present study evaluates the modulation of spatial and working memory with the Barnes Maze following a subchronic treatment with a low dose (0.5 mg/kg) of WIN55,212-2 (WIN) in both the SCOP and SAP models of learning and memory deficit. In the SCOP model, the administration of WIN protects learning and memory impairment during the probe trial, recorded as the time spent in the target quadrant (WIN + SCOP: 78 ± 13 sec vs VEH + SCOP: 45 ± 3 sec; p ¿ 0.001). A similar effect of the treatment was observed in the SAP model (SAP: 50 ± 3 sec vs SAP + WIN: 82 ± 7 sec; p ¿ 0.001). This effect was specifically mediated by CB1 receptors, since it was blocked by the co-administration of the specific CB1 antagonist, SR141716A (0.5 mg/kg) (SAP: 49 ± 3 sec vs SAP + WIN + SR: 48 ± 5 sec). However, higher doses of WIN (3 mg/kg) induced negative effects in learning and memory in control (C) rats, but positive and comparable to the lower dose in the SAP model (C: 89 ± 3 sec, C + WIN-3 mg/kg: 48 ± 3 sec; SAP: 49 ± 3; SAP + WIN-3 mg/kg: 80 ± 12 sec).The CB1 activation by low doses of the cannabinoid agonist WIN are able to block the amnesic effects induced by SCOP and also the learning and memory impairment produced by the BFCS pathway degeneration. CB1 agonists could contribute to improve the clinical symptoms of AD

Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction

214 p.The selective vulnerability of the basal forebrain cholinergic system (BFCS) is responsible for most of the clinical alterations in learning and memory processes that are characteristic of the Alzheimer¿s disease (AD). The loss of cholinergic neurons and muscarinic receptors (MR) in the nucleus basalis of Meynert has been reported in AD. The endocannabinoid system is a neuromodulator of the BFCS, but there are controversial reports regarding the cannabinoid effects in learning and memory processes.The animal models of cholinergic impairment mimick the main histopathological and behavioral effects observed in patients. The MR antagonism, e.g. using scopolamine (SCOP), is used as a model of amnesia in rodents. The intraparenchymal administration of 192-IgG-saporin (SAP) in the nucleus basalis magnocellularis eliminates cholinergic neurons leading to learning and memory deficits.Then, the present study evaluates the modulation of spatial and working memory with the Barnes Maze following a subchronic treatment with a low dose (0.5 mg/kg) of WIN55,212-2 (WIN) in both the SCOP and SAP models of learning and memory deficit. In the SCOP model, the administration of WIN protects learning and memory impairment during the probe trial, recorded as the time spent in the target quadrant (WIN + SCOP: 78 ± 13 sec vs VEH + SCOP: 45 ± 3 sec; p ¿ 0.001). A similar effect of the treatment was observed in the SAP model (SAP: 50 ± 3 sec vs SAP + WIN: 82 ± 7 sec; p ¿ 0.001). This effect was specifically mediated by CB1 receptors, since it was blocked by the co-administration of the specific CB1 antagonist, SR141716A (0.5 mg/kg) (SAP: 49 ± 3 sec vs SAP + WIN + SR: 48 ± 5 sec). However, higher doses of WIN (3 mg/kg) induced negative effects in learning and memory in control (C) rats, but positive and comparable to the lower dose in the SAP model (C: 89 ± 3 sec, C + WIN-3 mg/kg: 48 ± 3 sec; SAP: 49 ± 3; SAP + WIN-3 mg/kg: 80 ± 12 sec).The CB1 activation by low doses of the cannabinoid agonist WIN are able to block the amnesic effects induced by SCOP and also the learning and memory impairment produced by the BFCS pathway degeneration. CB1 agonists could contribute to improve the clinical symptoms of AD

The endocannabinoid system in experimental models of Alzheimer's disease

415 p.Durante la progresión de la enfermedad de Alzheimer (EA) se produce una degeneración del sistema de neurotransmisión colinérgico del prosencéfalo basal, que conduce a una pérdida progresiva e irreversible de funciones cognitivas, así como alteraciones del sistema endocannabinoide (eCB) y cambios en la composición lipídica cerebral. Cada vez más estudios apuntan al posible papel neuroprotector del sistema eCB en procesos neurodegenerativos y ya han sido demostrados los efectos beneficiosos de agonistas cannabinoides para el tratamiento de alteraciones conductuales asociadas a la EA. El sistema eCB modula entre otros al sistema colinérgico a través del receptor CB1 y, la síntesis de sus ligandos está ligada a la señalización muscarínica colinérgica en áreas que controlan procesos cognitivos. En este trabajo se ha estudiado el papel del sistema eCB en diferentes modelos de degeneración colinérgica y de EA. La inmunotoxina 192IgG-saporina elimina específicamente neuronas colinérgicas del prosencéfalo basal y se ha utilizado en cultivos organotípicos y ratas adultas como modelos ex vivo e in vivo de EA. Además se han administrado cannabinoides en el modelo 3xTg-AD para la EA y evaluado aprendizaje y memoria. El tratamiento con cannabinoides muestra protección sobre la muerte celular asociada a la lesión colinérgica en el modelo ex vivo. Los estudios in vivo, tras la administración de la inmunotoxina, muestran un deterioro cognitivo, una gran pérdida de inervación colinérgica cortical, un proceso adaptativo del sistema eCB a través del receptor CB1 y una profunda alteración del perfil fosfolipídico, todo ello asociado a la lesión colinérgica. El modelo 3xTg-AD presenta alteraciones conductuales asociadas a una desregulación del sistema eCB, que son parcialmente revertidas tras la activación subcrónica del receptor CB1. Proponemos al sistema eCB como modulador de la neurotransmisión colinérgica en neurodegeneración y potencial diana de intervención terapéutica en la EA

The endocannabinoid system in experimental models of Alzheimer's disease

415 p.Durante la progresión de la enfermedad de Alzheimer (EA) se produce una degeneración del sistema de neurotransmisión colinérgico del prosencéfalo basal, que conduce a una pérdida progresiva e irreversible de funciones cognitivas, así como alteraciones del sistema endocannabinoide (eCB) y cambios en la composición lipídica cerebral. Cada vez más estudios apuntan al posible papel neuroprotector del sistema eCB en procesos neurodegenerativos y ya han sido demostrados los efectos beneficiosos de agonistas cannabinoides para el tratamiento de alteraciones conductuales asociadas a la EA. El sistema eCB modula entre otros al sistema colinérgico a través del receptor CB1 y, la síntesis de sus ligandos está ligada a la señalización muscarínica colinérgica en áreas que controlan procesos cognitivos. En este trabajo se ha estudiado el papel del sistema eCB en diferentes modelos de degeneración colinérgica y de EA. La inmunotoxina 192IgG-saporina elimina específicamente neuronas colinérgicas del prosencéfalo basal y se ha utilizado en cultivos organotípicos y ratas adultas como modelos ex vivo e in vivo de EA. Además se han administrado cannabinoides en el modelo 3xTg-AD para la EA y evaluado aprendizaje y memoria. El tratamiento con cannabinoides muestra protección sobre la muerte celular asociada a la lesión colinérgica en el modelo ex vivo. Los estudios in vivo, tras la administración de la inmunotoxina, muestran un deterioro cognitivo, una gran pérdida de inervación colinérgica cortical, un proceso adaptativo del sistema eCB a través del receptor CB1 y una profunda alteración del perfil fosfolipídico, todo ello asociado a la lesión colinérgica. El modelo 3xTg-AD presenta alteraciones conductuales asociadas a una desregulación del sistema eCB, que son parcialmente revertidas tras la activación subcrónica del receptor CB1. Proponemos al sistema eCB como modulador de la neurotransmisión colinérgica en neurodegeneración y potencial diana de intervención terapéutica en la EA