Experimental Neurology最新文献

{"title":"Absence of pretaporter restrains features of the parkin phenotype in Drosophila","authors":"María Constanza Silvera ,&nbsp;Rafael Cantera ,&nbsp;María José Ferreiro","doi":"10.1016/j.expneurol.2024.114997","DOIUrl":"10.1016/j.expneurol.2024.114997","url":null,"abstract":"<div><h3>Background</h3><div>Scientific research based on model organisms can help to understand the biology of Parkinson's Disease, the second most prevalent neurodegenerative disease. <em>Drosophila melanogaster</em> mutant for the gene <em>parkin</em>, homologous to human's <em>PARK2</em>, exhibit well-characterized phenotypes including loss of dopaminergic neurons, lower survival and motor defects. Through the transcriptomic analysis of an exceptional case of reversible neurodegeneration in <em>Drosophila,</em> our group identified that the gene <em>pretaporter,</em> homologous to <em>TXNDC5</em> of humans, was downregulated in the reversal phase. Here, we explore the hypothesis that the lack of expression of <em>pretaporter</em> will restrain phenotypes observed in <em>Drosophila parkin</em> mutants.</div></div><div><h3>Methods</h3><div>After establishing by immunochemistry that Pretaporter is expressed in PPL1 dopaminergic neurons, we constructed <em>pretaporter-parkin</em> double mutants flies to investigate the hypothesis through immunohistochemistry, survival and climbing assays.</div></div><div><h3>Conclusions</h3><div>It was found that the loss-of-function mutation in <em>pretaporter</em> significatively restrains the phenotype caused by the loss-of-function mutation in <em>parkin</em> in several key aspects: it abolished the loss of PPL1 neurons normally seen in <em>parkin</em> mutant flies, promoted their survival in both sexes and reduced the decay in motor ability in <em>parkin</em> female flies. We propose that the absence of Pretaporter in <em>parkin</em> mutant flies prevents the death of dopaminergic neurons by rendering them resistant to Draper-mediated-phagocytosis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The zona incerta system: Involvement in Parkinson's disease","authors":"Yaying Shi ,&nbsp;Jing Zhang ,&nbsp;Minxia Xiu,&nbsp;Ruyi Xie,&nbsp;Yanhong Liu,&nbsp;Junxia Xie,&nbsp;Limin Shi","doi":"10.1016/j.expneurol.2024.114992","DOIUrl":"10.1016/j.expneurol.2024.114992","url":null,"abstract":"<div><div>Parkinson's disease (PD) is characterized by degeneration of the nigrostriatal dopamine system, resulting in progressive motor and nonmotor symptoms. Although most studies have focused on the basal ganglia network, recent evidence suggests that the zona incerta (ZI), a subthalamic structure composed of 4 neurochemically defined regions, is emerging as a therapeutic target in PD. This review summarizes the clinical and animal studies that indicate the importance of ZI in PD. Human clinical studies have shown that subthalamotomy or deep brain stimulation (DBS) of the ZI alleviates muscle rigidity, bradykinesia, tremors and speech dysfunction in patients with PD. Researchers have also studied the impact of DBS of the ZI on nonmotor signs such as pain, anxiety, and depression. Animal studies combining optogenetics, chemogenetics, behavioral assays, and neural activity recordings reveal the functional roles of ZI GABAergic and glutamatergic neurons in locomotion, gait, and coordination of the symptoms of PD, all of which are discussed in this review. Controversies and possible future studies are also discussed.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential evaluation of neuromuscular injuries to understand re-innervation at the neuromuscular junction","authors":"Daniel B. Hoffman ,&nbsp;Christiana J. Raymond-Pope ,&nbsp;Emma E. Pritchard ,&nbsp;Angela S. Bruzina ,&nbsp;Thomas J. Lillquist ,&nbsp;Benjamin T. Corona ,&nbsp;Jarrod A. Call ,&nbsp;Sarah M. Greising","doi":"10.1016/j.expneurol.2024.114996","DOIUrl":"10.1016/j.expneurol.2024.114996","url":null,"abstract":"<div><div>Peripheral nerve-crush injury is a well-established model of neuromuscular junction (NMJ) denervation and subsequent re-innervation. Functionally, the skeletal muscle follows a similar pattern as neural recovery, with immediate loss of force production that steadily improves in parallel with rates of re-innervation. On the other hand, traumatic injury to the muscle itself, specifically volumetric muscle loss (VML), results in an irrecoverable loss of muscle function. Recent work has indicated significant impairments to the NMJ following this injury that appear chronic in nature, alongside the lack of functional recovery. Thus, the goal of this study was to compare the effects of nerve and muscle injury on NMJ remodeling. Even numbers of adult male and female mice were used with three experimental groups: injury Naïve, nerve crush, and VML injury; and three terminal timepoints: 3-, 48-, and 112-days post-injury. Confirming the assumed recoverability of the two injury models, we found <em>in vivo</em> maximal torque was fully restored following nerve-crush injury but remained at a significant deficit following VML. Compared to injury Naïve and nerve-crush injury, we found VML results in aberrantly high trophic signaling (<em>e.g.</em>, neuregulin-1) and numbers of supporting cells, including terminal Schwann cells and sub-synaptic nuclei. In some cases, sex differences were detected, including higher rates of innervation in females than males. Both nerve crush and VML injury display chronic changes to NMJ morphology, such as increased fragmentation and nerve sprouting, highlighting the potential of VML for modeling NMJ regeneration in adulthood, alongside the established nerve-injury models.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An infrastructure for qualified data sharing and team science in late-stage translational spinal cord injury research","authors":"J. Russell Huie ,&nbsp;Abel Torres-Espin ,&nbsp;Jeffrey Sacramento ,&nbsp;Anastasia V. Keller ,&nbsp;Wilsaan M. Joiner ,&nbsp;Ryan North ,&nbsp;David J. Reinkensmeyer ,&nbsp;Ephron S. Rosenzweig ,&nbsp;Jacob Koffler ,&nbsp;Mark H. Tuszynski ,&nbsp;Carolyn J. Sparrey ,&nbsp;Jessica L. Nielson ,&nbsp;Michael S. Beattie ,&nbsp;Jacqueline C. Bresnahan ,&nbsp;Jeffrey S. Grethe ,&nbsp;Adam R. Ferguson","doi":"10.1016/j.expneurol.2024.114995","DOIUrl":"10.1016/j.expneurol.2024.114995","url":null,"abstract":"<div><div>The complex and heterogeneous nature of spinal cord injury has limited translational bench-to-bedside results. The wide variety of data, including injury parameters, biochemical, histological, and behavioral outcome measures represent a ‘big data’ problem, calling for modern data science solutions. There are some instances in which SCI researchers collect sensitive data that needs to remain private, such as datasets designed to meet regulatory approval, sensitive intellectual property, and non-human primate studies. For these types of data, we have developed a Private Data Commons for SCI (PDC-SCI). Our objective is to give an overview of this novel data commons, describing how this type of commons works, how it can benefit the research community, and the cases in which it would be most useful. This private infrastructure is ideal for multi-lab transdisciplinary studies that require a well-organized, scalable data commons for rapid data sharing within a closed, distributed team. As a use-case for the PDC-SCI, we demonstrate the VA Gordon Mansfield SCI Consortium, in which multimodal data from behavior, biomechanics of injury, hospital records, imaging, and histology are integrated, shared, and analyzed to facilitate insights and knowledge discovery.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective agents ineffective in mitigating autonomic dysreflexia following experimental spinal cord injury","authors":"Tamila Kalimullina ,&nbsp;Rahul Sachdeva ,&nbsp;Kiran Pawar ,&nbsp;Steven Cao ,&nbsp;Arshdeep Marwaha ,&nbsp;Jie Liu ,&nbsp;Ward Plunet ,&nbsp;Jordan Squair ,&nbsp;Christopher R. West ,&nbsp;Wolfram Tetzlaff ,&nbsp;Andrei V. Krassioukov","doi":"10.1016/j.expneurol.2024.114993","DOIUrl":"10.1016/j.expneurol.2024.114993","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Loss of supraspinal cardiovascular control and secondary damage following spinal cord injury (SCI) lead to cardiovascular dysfunction, where autonomic dysreflexia (AD), triggered by stimuli below the injury, can cause uncontrolled blood pressure (BP) surges, posing severe health risks such as stroke and seizures. While anti-inflammatory neuroprotective agents have been studied for motor recovery, their impact on cardiovascular function remains under investigated. The objective was to assess the efficacy of four clinically approved neuroprotective agents in promoting cardiovascular recovery following SCI.</div></div><div><h3>Methods</h3><div>Male Wistar rats received contusion at the third thoracic spinal segment (T3). Fluoxetine, Glyburide, Valproic acid, and Indomethacin were first administered at 1 h or 6 h post-SCI, and every 12 h for two weeks thereafter. Four weeks following SCI, hemodynamics were measured at rest and during colorectal distension. Locomotor function was assessed prior to SCI and weekly for four weeks after SCI, using the Basso-Beattie-Bresnahan (BBB) locomotor scale. Quantitative comparisons of lesion area were performed.</div></div><div><h3>Results</h3><div>Contrary to the published literature, Indomethacin and Valproic acid resulted in high morbidity and mortality rates 60 % and 40 % respectively) within 2–3 days of administration. Fluoxetine, and Glyburide were well-tolerated. There were no differences in change in systolic BP with colorectal distension compared to control i.e., all experimental groups experienced severe episodes of AD [F(6, 67) = 0.94, <em>p</em> = 0.47]. There was no significant difference in BBB scores in any experimental group compared to control [F(18, 252) = 0.3, <em>p</em> = 0.99]. No between-group differences were observed in tissue sparing at the lesion epicentre [F(6, 422) = 6.98, <em>p</em> = 0.29].</div></div><div><h3>Discussion</h3><div>Despite promising beneficial effect reported in previous studies, none of the drugs demonstrated improvement in cardiovascular or motor function. Indomethacin and Valproic acid exhibited unexpected high mortality at doses deemed safe in the literature. This emphasizes the necessity for reproducibility studies in pre-clinical research and underscores the importance of publishing null findings to guide future investigations.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-operative environmental enrichment does not yield a prophylactic effect against traumatic brain injury-induced neurobehavioral deficits","authors":"Eleni H. Moschonas ,&nbsp;Jade A. Steber ,&nbsp;Haley E. Capeci ,&nbsp;Hailey M. Donald ,&nbsp;Vincent J. Vozzella ,&nbsp;Rachel A. Bittner ,&nbsp;Ellen M. Annas ,&nbsp;Piper L. Rennerfeldt ,&nbsp;Jeffrey P. Cheng ,&nbsp;Corina O. Bondi ,&nbsp;Anthony E. Kline","doi":"10.1016/j.expneurol.2024.114990","DOIUrl":"10.1016/j.expneurol.2024.114990","url":null,"abstract":"<div><div>The robustness of environmental enrichment (EE) in ameliorating neurobehavioral and cognitive deficits after experimental traumatic brain injury (TBI) is unequivocal. What is equivocal is whether EE can function as a prophylactic to afford resiliency and neuroprotection against TBI. We hypothesized that pre-operative EE would yield a protective effect against TBI-induced motor, cognitive, and coping deficits, and that further improvements would be conferred when EE is provided before and after TBI. To test the hypotheses, adult male rats received either 4 weeks of EE or standard (STD) housing prior to undergoing a controlled cortical impact of moderate severity (2.8 mm deformation at 4 m/s) or sham injury while under anesthesia. After injury, the rats were randomly assigned to post-operative EE or STD housing. Motor ability, spatial learning, and memory retention were assessed by beam-walk and water maze tests, respectively. Active and passive behavioral coping strategies were evaluated with the shock probe defensive burying (SPDB) test. c-Fos and cortical lesion volume were also quantified. The post-TBI enrichment groups (EE + TBI + EE and STD + TBI + EE) did not differ (<em>p</em> &gt; 0.05) and performed better than the post-TBI STD-housed groups (EE + TBI + STD and STD + TBI + STD) on motor and cognition (<em>p</em> &lt; 0.05). The post-TBI STD groups did not differ, regardless of whether in EE or STD living conditions before injury (<em>p</em> &gt; 0.05). Moreover, both post-TBI enrichment groups performed better in the SPDB test relative to the STD + TBI + STD group (<em>p</em> &lt; 0.05). c-Fos + cells were upregulated in the ipsilateral CA₁ in both pre-injury EE groups relative to the pre-injury STD groups (<em>p</em> &lt; 0.05). No statistical differences were observed in cortical lesion volume among the groups. Overall, these data do not support the hypothesis as no neuroprotective effect was observed with 4 weeks of pre-operative EE and no additional benefit was achieved in the TBI group receiving both pre-and-post EE relative to the TBI group receiving only post-EE. However, the data do reinforce the consistency of post-TBI EE in producing robust neurobehavioral benefits, which further supports this paradigm as a relevant preclinical model of neurorehabilitation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential impact of optogenetic stimulation of direct and indirect pathways from dorsolateral and dorsomedial striatum on motor symptoms in Huntington's disease mice","authors":"Sara Conde-Berriozabal ,&nbsp;Laia Sitjà-Roqueta ,&nbsp;Esther García-García ,&nbsp;Lia García-Gilabert ,&nbsp;Anna Sancho-Balsells ,&nbsp;Sara Fernández-García ,&nbsp;Ened Rodriguez-Urgellés ,&nbsp;Albert Giralt ,&nbsp;Anna Castañé ,&nbsp;Manuel J. Rodríguez ,&nbsp;Jordi Alberch ,&nbsp;Mercè Masana","doi":"10.1016/j.expneurol.2024.114991","DOIUrl":"10.1016/j.expneurol.2024.114991","url":null,"abstract":"<div><div>The alterations in the basal ganglia circuitry are core pathological hallmark in Huntington's Disease (HD) and traditionally linked to its sever motor symptoms. Recently it was shown that optogenetic stimulation of cortical afferences to the striatum is able to reverse motor symptoms in HD mice. However, the specific contribution of the direct and indirect striatal output pathways from the dorsolateral (DLS) and dorsomedial striatum (DMS) to the motor phenotype is still not clear. Here, we aim to uncover the contributions of these striatal subcircuits to motor control in wild type (WT) and HD mice by using the symptomatic R6/1 mice. We systematically evaluated locomotion, exploratory behavior, and motor learning effects of the selective optogenetic stimulation of D1 or A2A expressing neurons (direct and indirect pathway, respectively), in DLS or DMS. Bilateral optogenetic stimulation of the direct pathway from DLS and the indirect pathway from DMS resulted in subtle locomotor enhancements, while unaltering exploratory behavior. Additionally, bilateral stimulation of the indirect pathway from the DLS improved performance in the accelerated rotarod task, suggesting a role in motor learning. In contrast, in HD mice, stimulation of these pathways did not modulate any of these behaviors. Overall, this study highlights that selective stimulation of direct and indirect pathways from DLS and DMS have subtle impact in locomotion, exploratory activity or motor learning. The lack of responses in HD mice also suggests that strategies involving cortico-striatal circuits rather than striatal output circuits might be a better strategy for managing motor symptoms in movement disorders.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotection of celastrol against postoperative cognitive dysfunction through dampening cGAS-STING signaling","authors":"Xueshan Bu ,&nbsp;Hui Guo ,&nbsp;Wenwei Gao ,&nbsp;Lei Zhang ,&nbsp;Jiabao Hou ,&nbsp;Bixi Li ,&nbsp;Zhongyuan Xia ,&nbsp;Wei Wang","doi":"10.1016/j.expneurol.2024.114987","DOIUrl":"10.1016/j.expneurol.2024.114987","url":null,"abstract":"<div><div>Neuroinflammation is a central player in postoperative cognitive dysfunction (POCD), an intractable and highly confounding neurological complication with finite therapeutic options. Celastrol, a quinone methide triterpenoid, is a bioactive ingredient extracted from Tripterygium wilfordii with talented anti-inflammatory capacity. However, it is unclear whether celastrol can prevent anesthesia/surgery-evoked cognitive deficits in an inflammation-specific manner. The STING agonist 5,6-dimethylxanthenone-4-acetic acid (DMXAA) was used to determine whether celastrol possesses neuroprotection dependent on the STING pathway in vivo and in vitro. Isoflurane and laparotomy triggered cGAS-STING activation, caspase-3/GSDME-dependent pyroptosis, and enhanced Iba-1 immunoreactivity. Celastrol improved cognitive performance and decreased the levels of cGAS, 2′3′-cGAMP, STING, NF-κB phosphorylation, Iba-1, TNF-α, IL-6, and IFN-β. Downregulation of cleaved caspase-3 and N-GSDME was observed in the hippocampus of POCD mice and HT22 cells after celastrol administration, accompanied by limited secretion of pyroptosis-pertinent pro-inflammatory cytokines IL-1β and IL-18. DMXAA neutralized the favorable influences of celastrol on cognitive function, as confirmed by the activation of the STING/caspase-3/GSDME axis. These findings implicate celastrol as a therapeutic agent for POCD through anti-inflammation and anti-pyroptosis.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of chaperone-mediated autophagy exerting neuroprotection effect on intracerebral hemorrhage-induced neuronal injury by targeting Lamp2a","authors":"Yun Zheng ,&nbsp;Lu Peng ,&nbsp;Guannan Jiang ,&nbsp;Jialei Zhou ,&nbsp;Siyuan Yang ,&nbsp;Lei Bai ,&nbsp;Xiang Li Sr ,&nbsp;Mingqing He","doi":"10.1016/j.expneurol.2024.114986","DOIUrl":"10.1016/j.expneurol.2024.114986","url":null,"abstract":"<div><div>Intracerebral hemorrhage (ICH) is a common and devastating type of stroke, marked by significant morbidity and a grim prognosis. The inflammation cascade triggered by astrocytes plays a critical role in secondary brain injury (SBI) following ICH, leading to detrimental effects such as cell death. However, effective intervention strategies are currently lacking. This study aims to investigate the role of the astrocyte cascade reaction following ICH and identify potential intervention targets. Utilizing the GSE216607 and GSE206971 databases for analysis, we established a mouse autologous blood model. Firstly, our research revealed a significant activation of the autophagy pathway following intracerebral hemorrhage (ICH), with a notable upregulation of Lamp2a, a key factor in chaperone-mediated autophagy (CMA), primarily localized in astrocytes. Additionally, the downregulation of Lamp2a resulted in a significant augmentation of A1 reactive astrocytes, concomitant with a reduction in myelin coverage area, heightened neuronal injury, exacerbated motor and sensory deficits, and diminished neurological scores after ICH in mice. Conversely, CA77.1, an activator of CMA, could reverse ICH-induced augmentation of A1 reactive astrocytes, myelin damage, neuronal death, and neurobehavioral disorders. In conclusion, the activation of astrocyte CMA following ICH can exert neuroprotective effects. Lamp2a represents a promising therapeutic target for post-ICH treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nabiximols (NBX) suppresses tremor in a rat Harmaline model of essential tremor","authors":"Sally Loomis,&nbsp;Elena Samoylenko,&nbsp;David Virley,&nbsp;Andrew C. McCreary","doi":"10.1016/j.expneurol.2024.114988","DOIUrl":"10.1016/j.expneurol.2024.114988","url":null,"abstract":"<div><h3>Background</h3><div>Essential tremor (ET) is one of the most prevalent movement disorders; despite this, there remains an unmet need for novel therapies. The treatment of rats with harmaline modulates the rhythmicity of inferior olivary neurons, resulting in generalized tremor with a frequency of 9–12 Hz in rats, comparable to that of human ET (4–12 Hz).</div></div><div><h3>Purpose</h3><div>Interestingly, cannabinoids reduce tremor, therefore we have assessed the cannabinoid nabiximols (NBX; marketed as Sativex) a complex botanical drug mixture, in the harmaline-rat model of ET.</div></div><div><h3>Method</h3><div>We tested the effects of acute (single dose) and subchronic (10 days) treatment of NBX (at 5.2, 10.4 and 20.8 mg kg⁻¹ p.o.) administered prior to harmaline and acute NBX (20.8 mg kg⁻¹) administered post-harmaline in male SD rats. Propranolol (20 mg kg⁻¹ i.p.) was used as a positive control. Observed Scoring (OS) was carried out prior to placement in a tremor-monitoring apparatus for the calculation of Tremor Index (TI) and Motion Power Percentage (MPP).</div></div><div><h3>Results</h3><div>Acute and subchronic NBX significantly attenuated harmaline-induced tremor at 10.4 and 20.8 mg kg⁻¹, respectively, for each parameter (OS, TI, and MPP) when administered pre-harmaline as did propranolol (20 mg kg⁻¹). NBX did not attenuate harmaline-induced tremor when administered post-harmaline.</div></div><div><h3>Conclusions</h3><div>These data suggest efficacy of acute and subchronic NBX to reduce tremors, based on OS, TI and MPP readouts if administered prior to harmaline. These data are the first to indicate the preclinical effects of an oral botanical cannabinoid formulation, NBX, in an animal model of ET.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":4.6,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}