- 作者列表："Jiménez-Sánchez L","Blesa J","Del Rey NL","Monje MHG","Obeso JA","Cavada C
:Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra and dopamine depletion in the striatum. Non-dopaminergic systems are also affected, including the serotonergic system. Enhanced striatal serotonergic innervation is a proposed compensatory mechanism for the dopaminergic deficit. Meanwhile a serotonergic deficit has been suggested as preceding the nigrostriatal dopaminergic pathology in PD. Our aim was to assess the serotonergic innervation of the striatum in a model of progressive experimental parkinsonism in macaques, from pre-symptomatic to symptomatic stages. The neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) was administered to adult macaque monkeys using a slow intoxication protocol. The intoxicated animals were classified into asymptomatic, recovered, moderate and severe parkinsonian, based on their motor behavior. The serotonergic innervation was studied by immunohistochemistry against serotonin (5-HT). In the striatum, the density of 5-HT-immunoreactive (5-HT+) axons was estimated with stereology. Images of the striatum in the immunostained sections were taken to compare the distribution patterns of the serotonergic innervation between groups. These patterns were apparently similar among the groups. Axonal density estimations showed no differences in striatal 5-HT+ innervation between the intoxicated groups and the control group. Accordingly, this study fails to find significant changes in the striatal serotonergic axonal innervation in MPTP-treated monkeys, coinciding with previous biochemical findings in our model. However, it is possible that alterations in the serotonergic system in PD could be independent of axonal density changes. Consequently, the proposed role for striatal serotonin serving as a compensatory mechanism for dopaminergic denervation merits further study. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
: 帕金森病 (Parkinson's disease，PD) 以黑质多巴胺能神经变性和纹状体多巴胺耗竭为特征。非多巴胺能系统也受到影响，包括 5-羟色胺能系统。增强纹状体 5-羟色胺能神经支配是多巴胺能缺陷的代偿机制。同时，在 PD 的黑质纹状体多巴胺能病理学研究中，已经提出了 5-羟色胺能缺陷。我们的目的是评估猕猴进行性实验性帕金森综合征模型中纹状体的 5-羟色胺能神经支配，从症状前到症状阶段。神经毒素 1-甲基-4-苯基-1，2,3，6 四氢吡啶 (MPTP) 使用缓慢中毒方案给予成年猕猴。根据运动行为将醉酒动物分为无症状、恢复、中度和重度帕金森病。通过抗 5-羟色胺 (5-HT) 的免疫组织化学研究 5-羟色胺能神经支配。在纹状体中，用体视学方法估计 5-HT 免疫反应 (5-HT +) 轴突的密度。取免疫染色切片中纹状体的图像，比较组间 5-羟色胺能神经支配的分布模式。这些模式在各组之间显然相似。轴突密度估计显示，中毒组和对照组之间纹状体 5-HT + 神经支配无差异。因此，本研究未能在 MPTP 处理的猴子中发现纹状体 5-羟色胺能轴突神经支配的显著变化，与我们模型中以前的生化发现一致。然而，PD 中 5-羟色胺能系统的改变可能与轴突密度的变化无关。因此，纹状体 5-羟色胺作为多巴胺能失神经支配的代偿机制的作用值得进一步研究。本文是题为 “血清素研究: 交叉尺度和界限” 的特刊的一部分。
METHODS::Identifying disease-causing pathways and drugs that target them in Parkinson's disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.
METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.
METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.