Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2025.e00542
Alban Latremoliere
{"title":"From a clinically relevant pain target to a possible analgesic treatment strategy","authors":"Alban Latremoliere","doi":"10.1016/j.neurot.2025.e00542","DOIUrl":"10.1016/j.neurot.2025.e00542","url":null,"abstract":"","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00542"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256131","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2024.e00496
Zhimin Huang , Ying Wang , Yongxing Yan , Ying Liu , Jielin Chen , Huili Liu , Jie Li , Zhongming Gao , Xianwei Che
Non-invasive brain stimulation (NIBS) technology such as transcranial magnetic stimulation (TMS) represents a promising treatment for neuropathic pain. However, neural circuitries underlying analgesia remain to be established, which is largely limiting treatment responses. Using TMS and electroencephalogram co-registration (TMS-EEG), this study quantified the circuitry abnormalities in neuropathic pain and their associations with pain symptoms. A group of 21 neuropathic pain individuals and 21 healthy controls were assessed with TMS-EEG delivering to the primary motor cortex (M1). With source modelling, local current density and current propagation were analysed with significant current density (SCD) and scattering (SCS) respectively. The SCS and SCD data converged on higher activities in neuropathic pain individuals than healthy controls, within the emotional affective (perigenual anterior cingulate cortex, pgACC), sensory nociceptive (primary somatosensory cortex, S1), and the attentional cognitive (anterior insula, aINS; supracallosal anterior cingulate cortex, scACC) structures of pain. Moreover, current propagation to the pgACC was associated with lower pain-related negative emotions, while current propagation to the aINS with higher pain-related negative emotions. Using concurrent TMS-EEG, our data identified abnormal pain circuitries that could be utilised to improve treatment efficacy with brain stimulation technologies.
{"title":"Identifying neural circuitry abnormalities in neuropathic pain with transcranial magnetic stimulation and electroencephalogram co-registration","authors":"Zhimin Huang , Ying Wang , Yongxing Yan , Ying Liu , Jielin Chen , Huili Liu , Jie Li , Zhongming Gao , Xianwei Che","doi":"10.1016/j.neurot.2024.e00496","DOIUrl":"10.1016/j.neurot.2024.e00496","url":null,"abstract":"<div><div>Non-invasive brain stimulation (NIBS) technology such as transcranial magnetic stimulation (TMS) represents a promising treatment for neuropathic pain. However, neural circuitries underlying analgesia remain to be established, which is largely limiting treatment responses. Using TMS and electroencephalogram co-registration (TMS-EEG), this study quantified the circuitry abnormalities in neuropathic pain and their associations with pain symptoms. A group of 21 neuropathic pain individuals and 21 healthy controls were assessed with TMS-EEG delivering to the primary motor cortex (M1). With source modelling, local current density and current propagation were analysed with significant current density (SCD) and scattering (SCS) respectively. The SCS and SCD data converged on higher activities in neuropathic pain individuals than healthy controls, within the emotional affective (perigenual anterior cingulate cortex, pgACC), sensory nociceptive (primary somatosensory cortex, S1), and the attentional cognitive (anterior insula, aINS; supracallosal anterior cingulate cortex, scACC) structures of pain. Moreover, current propagation to the pgACC was associated with lower pain-related negative emotions, while current propagation to the aINS with higher pain-related negative emotions. Using concurrent TMS-EEG, our data identified abnormal pain circuitries that could be utilised to improve treatment efficacy with brain stimulation technologies.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00496"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754949","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2025.e00528
Soshi Samejima , Raza N. Malik , Jennifer Ge , Lucas Rempel , Kawami Cao , Sameer Desai , Claire Shackleton , Anahita Kyani , Parisa Sarikhani , Jessica M. D'Amico , Andrei V. Krassioukov
This study evaluated whether cervical transcutaneous spinal cord stimulation (tSCS) in conjunction with rehabilitation on upper extremity function alters blood pressure regulation in individuals with cervical spinal cord injury. This study is a secondary analysis of the Up-LIFT trial, a prospective single-arm multicenter trial designed to evaluate the safety and efficacy of tSCS in conjunction with rehabilitation (tSCS + rehab) on upper extremity function in individuals with chronic cervical spinal cord injury. Utilizing this large data set obtained from 60 individuals across 14 international sites, we compared blood pressure and heart rate measurements obtained before, during and after each training session during both the wash-in Rehab alone period and the tSCS + rehab period of the trial. Blood pressure and heart rate were recorded during each session throughout the protocol in all participants. Sessions of tSCS + rehab did not cause significant changes in blood pressure or heart rate compared to Rehab alone (p > 0.05). Further, blood pressure medications did not have an effect on these cardiovascular responses to tSCS (p > 0.05). This study supports the safety profile of cervical tSCS paired with rehabilitation in individuals with cervical spinal cord injury. The lack of adverse effects on blood pressure and heart rate during the intervention, together with the previously reported clinically meaningful improvements in upper extremity strength and function strongly supports the utility of tSCS in this patient population. Further work is required to elucidate potential long-term effects of targeted tSCS on cardiovascular function in people with spinal cord injury.
{"title":"Cardiovascular safety of transcutaneous spinal cord stimulation in cervical spinal cord injury","authors":"Soshi Samejima , Raza N. Malik , Jennifer Ge , Lucas Rempel , Kawami Cao , Sameer Desai , Claire Shackleton , Anahita Kyani , Parisa Sarikhani , Jessica M. D'Amico , Andrei V. Krassioukov","doi":"10.1016/j.neurot.2025.e00528","DOIUrl":"10.1016/j.neurot.2025.e00528","url":null,"abstract":"<div><div>This study evaluated whether cervical transcutaneous spinal cord stimulation (tSCS) in conjunction with rehabilitation on upper extremity function alters blood pressure regulation in individuals with cervical spinal cord injury. This study is a secondary analysis of the Up-LIFT trial, a prospective single-arm multicenter trial designed to evaluate the safety and efficacy of tSCS in conjunction with rehabilitation (tSCS + rehab) on upper extremity function in individuals with chronic cervical spinal cord injury. Utilizing this large data set obtained from 60 individuals across 14 international sites, we compared blood pressure and heart rate measurements obtained before, during and after each training session during both the wash-in Rehab alone period and the tSCS + rehab period of the trial. Blood pressure and heart rate were recorded during each session throughout the protocol in all participants. Sessions of tSCS + rehab did not cause significant changes in blood pressure or heart rate compared to Rehab alone (p > 0.05). Further, blood pressure medications did not have an effect on these cardiovascular responses to tSCS (p > 0.05). This study supports the safety profile of cervical tSCS paired with rehabilitation in individuals with cervical spinal cord injury. The lack of adverse effects on blood pressure and heart rate during the intervention, together with the previously reported clinically meaningful improvements in upper extremity strength and function strongly supports the utility of tSCS in this patient population. Further work is required to elucidate potential long-term effects of targeted tSCS on cardiovascular function in people with spinal cord injury.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00528"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075178","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}
Microvascular dysfunction and no-reflow are considered a major cause of secondary damage despite revascularization in acute ischemic stroke (AIS), ultimately affecting patient outcomes. We used quantitative PET-MRI imaging to characterize early microvascular damages in a preclinical non-human primate model mimicking endovascular mechanical thrombectomy (EVT). During occlusion, PET perfusion and MRI diffusion were used to measure ischemic and lesion core volumes respectively. Following revascularization, multiparametric PET-MRI included perfusion, diffusion, blood-brain barrier (BBB) permeability MRI, and 15O-oxygen metabolism PET. Lesion growth on MRI was evaluated at one week, and the neurological score was assessed daily; a poor outcome was defined as a score>6 (0-normal, 60-death) after one week. Early after recanalization, the gold-standard PET ischemic threshold (<0.2 mL/min/g) identified post-EVT hypoperfusion in 67 % of the cases (14/21) located in the occlusion acute lesion. Acquired 110 min post-EVT, the area of MRI Tmax hypoperfusion was larger and even more frequent (18/20) and was also located within the acute lesion. Eight of the total cases (38 %) had a poor outcome, and all of them had no-reflow (7/8 MRI no-reflow and 6/8 PET no-reflow). Diffusion ADC alterations and post-EVT oxygen extraction fraction (OEF) values were significantly different in PET no-reflow cases compared to those without no-reflow, exhibiting an inverse correlation. Independently of no-reflow, long perfusion Tmax and post-EVT high BBB Ktrans in the lesion core were the hallmarks of poor outcome and infarct growth. This early quantitative imaging signature may predict infarct growth and poor outcome and help to identify neuroprotection targets.
{"title":"Quantitative imaging outperforms No-reflow in predicting functional outcomes in a translational stroke model","authors":"Justine Debatisse , Lucie Chalet , Omer Faruk Eker , Tae-Hee Cho , Guillaume Becker , Océane Wateau , Marlène Wiart , Nicolas Costes , Inés Mérida , Christelle Léon , Jean-Baptiste Langlois , Sophie Lancelot , François Lux , Timothé Boutelier , Norbert Nighoghossian , Laura Mechtouff , Emmanuelle Canet-Soulas","doi":"10.1016/j.neurot.2025.e00529","DOIUrl":"10.1016/j.neurot.2025.e00529","url":null,"abstract":"<div><div>Microvascular dysfunction and no-reflow are considered a major cause of secondary damage despite revascularization in acute ischemic stroke (AIS), ultimately affecting patient outcomes. We used quantitative PET-MRI imaging to characterize early microvascular damages in a preclinical non-human primate model mimicking endovascular mechanical thrombectomy (EVT). During occlusion, PET perfusion and MRI diffusion were used to measure ischemic and lesion core volumes respectively. Following revascularization, multiparametric PET-MRI included perfusion, diffusion, blood-brain barrier (BBB) permeability MRI, and <sup>15</sup>O-oxygen metabolism PET. Lesion growth on MRI was evaluated at one week, and the neurological score was assessed daily; a poor outcome was defined as a score>6 (0-normal, 60-death) after one week. Early after recanalization, the gold-standard PET ischemic threshold (<0.2 mL/min/g) identified post-EVT hypoperfusion in 67 % of the cases (14/21) located in the occlusion acute lesion. Acquired 110 min post-EVT, the area of MRI <em>Tmax</em> hypoperfusion was larger and even more frequent (18/20) and was also located within the acute lesion. Eight of the total cases (38 %) had a poor outcome, and all of them had no-reflow (7/8 MRI no-reflow and 6/8 PET no-reflow). Diffusion <em>ADC</em> alterations and post-EVT oxygen extraction fraction (<em>OEF)</em> values were significantly different in PET no-reflow cases compared to those without no-reflow, exhibiting an inverse correlation. Independently of no-reflow, long perfusion <em>Tmax</em> and post-EVT high BBB <em>Ktrans</em> in the lesion core were the hallmarks of poor outcome and infarct growth. This early quantitative imaging signature may predict infarct growth and poor outcome and help to identify neuroprotection targets.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00529"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075189","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2025.e00544
Lucia Lage , Ana I. Rodriguez-Perez , Jose Luis Labandeira-Garcia , Antonio Dominguez-Meijide
ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.
{"title":"Fasudil inhibits α-synuclein aggregation through ROCK-inhibition-mediated mechanisms","authors":"Lucia Lage , Ana I. Rodriguez-Perez , Jose Luis Labandeira-Garcia , Antonio Dominguez-Meijide","doi":"10.1016/j.neurot.2025.e00544","DOIUrl":"10.1016/j.neurot.2025.e00544","url":null,"abstract":"<div><div>ROCK inhibitors such as fasudil protected against dopaminergic degeneration and other neurodegenerative processes in several experimental models through inhibition of neuroinflammation and activation of survival signaling pathways, and clinical trials have been initiated. More recently, fasudil has been suggested to inhibit α-synuclein aggregation. However, this is controversial, particularly if it is a consequence of direct binding of the fasudil molecule to α-synuclein. We studied the mechanisms involved in the effects of fasudil on α-synuclein aggregation using the α-synuclein-T/V5-synphilin-1 model. Molecule-molecule interactions were studied using real time quaking inducing conversion (RT-QuiC). Fasudil decreased the number of cells with inclusions and the size of inclusions in dopaminergic neurons and glial cells, and inhibited α-synuclein aggregation and microglial endocytosis of aggregates. These changes were not due to changes in α-synuclein protein expression or phosphorylation and were related to ROCK inhibition rather than direct interaction with α-synuclein, as confirmed with a second ROCK inhibitor (Y27632) and ROCK gene silencing. We observed that ROCK inhibition downregulates several factors that are known to promote α-synuclein aggregation such as NADPH-oxidase-derived oxidative stress, intracellular calcium increase, and α-synuclein endocytosis, and promotes autophagy. The present results support that fasudil is a useful drug against Parkinson's disease progression. In addition to other reported neuroprotective properties, fasudil inhibits α-synuclein aggregation and microglial endocytosis of aggregates, which enhances the microglial inflammatory response. The effects of fasudil are mostly related to ROCK inhibition, which we have shown using two structurally different ROCK inhibitors and knockdown data, and further supported by using RT-QuiC.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00544"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365157","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2025.e00541
Timothy E. O'Toole , Alok R. Amraotkar , Hong Gao , Clara G. Sears , Shesh N. Rai , Mathias Basner , Aruni Bhatnagar
Some prior studies suggested that supplementation with carnosine or β-alanine can improve cognitive abilities and neurodegenerative disorders in certain elderly or at-risk populations. However, the efficacy of carnosine in improving cognitive performance in a healthy, adult population has not been assessed. We examined this as a post-hoc secondary outcome in the placebo-controlled, randomized Nucleophilic Defense Against PM Toxicity (NEAT) clinical trial (NCT03314987). Participants in this trial were instructed to take either cornstarch (placebo) or carnosine capsules (2g daily) for up to 12wk. Cognitive ability was assessed using the Cognition test battery, which consists of ten individual tests known to engage specific brain systems and covering a range of cognitive domains. Speed, accuracy, and efficiency were obtained for the whole battery as well as for each of the ten individual tests. Participant testing occurred at baseline, prior to randomization, after approximately 6wk of supplementation (Follow-up-1), and after approximately 12wk of supplementation (Follow-up-2). Of the 299 participants who were randomized, we obtained useable measures for 242 participants at Follow-up-1 and 231 at Follow-up-2. Age-based stratification (23–35 years, 36–50 years, 51–65 years), showed statistically significant improvements in overall speed and efficiency in the youngest age group stratum at both follow-up visits. This same group also demonstrated significant improvements in seven speed or accuracy scores of the individual tests. The other age groups demonstrated few or no significant improvements. Thus, in a study population largely devoid of susceptibility factors or pre-existing conditions, carnosine supplementation selectively improved high-level cognitive performance in young individuals.
{"title":"Carnosine supplementation improves cognitive outcomes in younger participants of the NEAT trial","authors":"Timothy E. O'Toole , Alok R. Amraotkar , Hong Gao , Clara G. Sears , Shesh N. Rai , Mathias Basner , Aruni Bhatnagar","doi":"10.1016/j.neurot.2025.e00541","DOIUrl":"10.1016/j.neurot.2025.e00541","url":null,"abstract":"<div><div>Some prior studies suggested that supplementation with carnosine or β-alanine can improve cognitive abilities and neurodegenerative disorders in certain elderly or at-risk populations. However, the efficacy of carnosine in improving cognitive performance in a healthy, adult population has not been assessed. We examined this as a post-hoc secondary outcome in the placebo-controlled, randomized Nucleophilic Defense Against PM Toxicity (NEAT) clinical trial (NCT03314987). Participants in this trial were instructed to take either cornstarch (placebo) or carnosine capsules (2g daily) for up to 12wk. Cognitive ability was assessed using the <em>Cognition</em> test battery, which consists of ten individual tests known to engage specific brain systems and covering a range of cognitive domains. Speed, accuracy, and efficiency were obtained for the whole battery as well as for each of the ten individual tests. Participant testing occurred at baseline, prior to randomization, after approximately 6wk of supplementation (Follow-up-1), and after approximately 12wk of supplementation (Follow-up-2). Of the 299 participants who were randomized, we obtained useable measures for 242 participants at Follow-up-1 and 231 at Follow-up-2. Age-based stratification (23–35 years, 36–50 years, 51–65 years), showed statistically significant improvements in overall speed and efficiency in the youngest age group stratum at both follow-up visits. This same group also demonstrated significant improvements in seven speed or accuracy scores of the individual tests. The other age groups demonstrated few or no significant improvements. Thus, in a study population largely devoid of susceptibility factors or pre-existing conditions, carnosine supplementation selectively improved high-level cognitive performance in young individuals.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00541"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370891","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2024.e00510
Dag Sehlin , Sahar Roshanbin , Olof Zachrisson , Martin Ingelsson , Stina Syvänen
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential, but therapeutic efficacy is limited by poor brain penetration of antibodies. We developed a bispecific antibody, RmAb38E2-scFv8D3, based on αSYN oligomer selective RmAb38E2 fused to a transferrin receptor (TfR)-binding domain to enhance brain delivery. Both RmAb38E2 and RmAb38E2-scFv8D3 showed higher affinity for αSYN oligomers than for monomers or fibrils. In vivo, RmAb38E2-scFv8D3 exhibited higher brain and lower blood concentrations compared to RmAb38E2, suggesting a better brain uptake and reduced peripheral exposure for the bispecific antibody. Treatment over five days of 3–4 months old transgenic L61 mice, which overexpress human αSYN, with three doses of RmAb38E2-scFv8D3 reduced brain αSYN oligomer levels and increased microglial activation, as indicated by elevated soluble TREM2 levels. Treatment with the monospecific RmAb38E2, however, showed no significant effect compared to PBS. This study demonstrates that TfR-mediated delivery enhances the therapeutic potential of αSYN-targeted immunotherapy by resulting in a higher concentration and a more uniform distribution of antibodies in the brain. The use of bispecific antibodies offers a promising strategy to improve the efficacy of antibody therapies in PD and other α-synucleinopathies.
{"title":"A brain-penetrant bispecific antibody lowers oligomeric alpha-synuclein and activates microglia in a mouse model of alpha-synuclein pathology","authors":"Dag Sehlin , Sahar Roshanbin , Olof Zachrisson , Martin Ingelsson , Stina Syvänen","doi":"10.1016/j.neurot.2024.e00510","DOIUrl":"10.1016/j.neurot.2024.e00510","url":null,"abstract":"<div><div>Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential, but therapeutic efficacy is limited by poor brain penetration of antibodies. We developed a bispecific antibody, RmAb38E2-scFv8D3, based on αSYN oligomer selective RmAb38E2 fused to a transferrin receptor (TfR)-binding domain to enhance brain delivery. Both RmAb38E2 and RmAb38E2-scFv8D3 showed higher affinity for αSYN oligomers than for monomers or fibrils. <em>In vivo</em>, RmAb38E2-scFv8D3 exhibited higher brain and lower blood concentrations compared to RmAb38E2, suggesting a better brain uptake and reduced peripheral exposure for the bispecific antibody. Treatment over five days of 3–4 months old transgenic L61 mice, which overexpress human αSYN, with three doses of RmAb38E2-scFv8D3 reduced brain αSYN oligomer levels and increased microglial activation, as indicated by elevated soluble TREM2 levels. Treatment with the monospecific RmAb38E2, however, showed no significant effect compared to PBS. This study demonstrates that TfR-mediated delivery enhances the therapeutic potential of αSYN-targeted immunotherapy by resulting in a higher concentration and a more uniform distribution of antibodies in the brain. The use of bispecific antibodies offers a promising strategy to improve the efficacy of antibody therapies in PD and other α-synucleinopathies.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00510"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828757","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2024.e00518
Abrar Hakami , Sebastiano Antonio Rizzo , Oliver J.M. Bartley , Rachel Hills , Sophie V. Precious , Timothy Ostler , Marija Fjodorova , Majed Alghamdi , Anne E. Rosser , Emma L. Lane , Thomas E. Woolley , Mariah J. Lelos , Ben Newland
Replacing cells lost during the progression of neurodegenerative disorders holds potential as a therapeutic strategy. Unfortunately, the majority of cells die post-transplantation, which creates logistical and biological challenges for cell therapy approaches. The cause of cell death is likely to be multifactorial in nature but has previously been correlated with hypoxia in the graft core. Here we use mathematical modelling to highlight that grafted cells experiencing hypoxia will also face a rapid decline in glucose availability. Interestingly, three neuron progenitor types derived from stem cell sources, and primary human fetal ventral mesencephalic (VM) cells all remained highly viable in severe hypoxia (0.1 % oxygen), countering the idea of rapid hypoxia-induced death in grafts. However, we demonstrate that glucose deprivation, not a paucity of oxygen, was a driver of rapid cell death, which was compounded in ischemic conditions of both oxygen and glucose deprivation. Supplementation of glucose to rat embryonic VM cells transplanted to the adult rat brain failed to improve survival at the dose administered and highlighted the problems of using osmotic minipumps in assisting neural grafting. The data shows that maintaining sufficient glucose in grafts is likely to be of critical importance for cell survival, but better means of achieving sustained glucose delivery is required.
{"title":"Graft ischemia post cell transplantation to the brain: Glucose deprivation as the primary driver of rapid cell death","authors":"Abrar Hakami , Sebastiano Antonio Rizzo , Oliver J.M. Bartley , Rachel Hills , Sophie V. Precious , Timothy Ostler , Marija Fjodorova , Majed Alghamdi , Anne E. Rosser , Emma L. Lane , Thomas E. Woolley , Mariah J. Lelos , Ben Newland","doi":"10.1016/j.neurot.2024.e00518","DOIUrl":"10.1016/j.neurot.2024.e00518","url":null,"abstract":"<div><div>Replacing cells lost during the progression of neurodegenerative disorders holds potential as a therapeutic strategy. Unfortunately, the majority of cells die post-transplantation, which creates logistical and biological challenges for cell therapy approaches. The cause of cell death is likely to be multifactorial in nature but has previously been correlated with hypoxia in the graft core. Here we use mathematical modelling to highlight that grafted cells experiencing hypoxia will also face a rapid decline in glucose availability. Interestingly, three neuron progenitor types derived from stem cell sources, and primary human fetal ventral mesencephalic (VM) cells all remained highly viable in severe hypoxia (0.1 % oxygen), countering the idea of rapid hypoxia-induced death in grafts. However, we demonstrate that glucose deprivation, not a paucity of oxygen, was a driver of rapid cell death, which was compounded in ischemic conditions of both oxygen and glucose deprivation. Supplementation of glucose to rat embryonic VM cells transplanted to the adult rat brain failed to improve survival at the dose administered and highlighted the problems of using osmotic minipumps in assisting neural grafting. The data shows that maintaining sufficient glucose in grafts is likely to be of critical importance for cell survival, but better means of achieving sustained glucose delivery is required.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00518"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952130","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2025.e00531
Carlos A. Dallera , Fabiola Placeres-Uray , Patrizzia Mastromatteo-Alberga , Maria Dominguez-Torres , Alyssa F. Balleste , Aditi S. Gorthy , Tyler S. Rahimzadeh , Isabelle Aliancin , W. Dalton Dietrich , Juan Pablo de Rivero Vaccari , Irwin C. Jacobs , Elizabeth A. Chlipala , Hannah Benton , Michael A. Zeligs , Coleen M. Atkins
3,3′-Diindolylmethane (DIM), a naturally occurring bis-indole found in cruciferous vegetables and produced in small amounts in the normal flora of the human gut, has demonstrated neuroprotective benefits in models of CNS hypoxia and stroke. In the CNS, DIM modulates the activation of the aryl hydrocarbon receptor (AhR) and inhibits its pro-inflammatory effects. Although capable of crossing the blood brain barrier, DIM's bioavailability is limited by its low solubility. Dispersed BR4044 provides a nanoscale high-solubility DIM suspension with the potential for treating traumatic brain injury (TBI). The present study aimed to determine whether BR4044 treatment could reduce pathology and improve behavioral recovery following moderate TBI. Male Sprague Dawley rats received moderate fluid percussion injury or sham surgery followed by vehicle or BR4044 treatment in the acute recovery period. TBI BR4044 animals showed significantly reduced cortical and hippocampal edema and lower levels of serum-derived extracellular vesicles compared to TBI Vehicle animals. BR4044 treatment of TBI animals preserved sensorimotor function and associative fear memory. Cortical contusion size and neuronal loss in the parietal cortex and CA3 region of the hippocampus were also significantly reduced with BR4044 treatment. BR4044 also decreased microbleeding and nuclear AhR at the contusion site. This translational study demonstrates that BR4044 ameliorates pathology and improves neurological outcomes following TBI by reducing brain edema, lowering acute extracellular vesicle release, modulating AhR, preserving cortical and hippocampal neurons, reducing red blood cell (RBC) extravasation into the injured brain, and promoting behavioral recovery.
{"title":"3,3′-Diindolylmethane improves pathology and neurological outcome following traumatic brain injury","authors":"Carlos A. Dallera , Fabiola Placeres-Uray , Patrizzia Mastromatteo-Alberga , Maria Dominguez-Torres , Alyssa F. Balleste , Aditi S. Gorthy , Tyler S. Rahimzadeh , Isabelle Aliancin , W. Dalton Dietrich , Juan Pablo de Rivero Vaccari , Irwin C. Jacobs , Elizabeth A. Chlipala , Hannah Benton , Michael A. Zeligs , Coleen M. Atkins","doi":"10.1016/j.neurot.2025.e00531","DOIUrl":"10.1016/j.neurot.2025.e00531","url":null,"abstract":"<div><div>3,3′-Diindolylmethane (DIM), a naturally occurring bis-indole found in cruciferous vegetables and produced in small amounts in the normal flora of the human gut, has demonstrated neuroprotective benefits in models of CNS hypoxia and stroke. In the CNS, DIM modulates the activation of the aryl hydrocarbon receptor (AhR) and inhibits its pro-inflammatory effects. Although capable of crossing the blood brain barrier, DIM's bioavailability is limited by its low solubility. Dispersed BR4044 provides a nanoscale high-solubility DIM suspension with the potential for treating traumatic brain injury (TBI). The present study aimed to determine whether BR4044 treatment could reduce pathology and improve behavioral recovery following moderate TBI. Male Sprague Dawley rats received moderate fluid percussion injury or sham surgery followed by vehicle or BR4044 treatment in the acute recovery period. TBI BR4044 animals showed significantly reduced cortical and hippocampal edema and lower levels of serum-derived extracellular vesicles compared to TBI Vehicle animals. BR4044 treatment of TBI animals preserved sensorimotor function and associative fear memory. Cortical contusion size and neuronal loss in the parietal cortex and CA3 region of the hippocampus were also significantly reduced with BR4044 treatment. BR4044 also decreased microbleeding and nuclear AhR at the contusion site. This translational study demonstrates that BR4044 ameliorates pathology and improves neurological outcomes following TBI by reducing brain edema, lowering acute extracellular vesicle release, modulating AhR, preserving cortical and hippocampal neurons, reducing red blood cell (RBC) extravasation into the injured brain, and promoting behavioral recovery.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00531"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256130","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}
Pub Date : 2025-03-01DOI: 10.1016/j.neurot.2025.e00547
Ji Hyeon Kim , Sae Yeon Hwang , Hye-Lan Lee , Sol Lip Yoon , Yoon Ha , Hye Yeong Lee , Seungjun Ryu
Neuromodulation therapy using chemogenetic stimulation has shown potential in enhancing motor recovery and neuroregeneration following spinal cord injury (SCI). These therapeutic benefits are hypothesized to result from the promotion of neuroplasticity, particularly when administered during the acute phase of injury. In this study, we investigated the effects of chemogenetic stimulation using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in conjunction with clozapine, a ligand for receptor activation. DREADDs enable targeted, reversible neuromodulation, facilitating the histological characterization of engineered neurons. We utilized these receptors to modulate G-protein-coupled receptor (GPCR) signaling pathways, leading to the activation or inhibition of intracellular signaling. The objective was to determine whether the administration of DREADDs and clozapine (0.1 mg/kg) could enhance motor function and neuronal recovery, particularly when applied during the acute phase of SCI. Weekly behavioral assessments demonstrated significant improvements in motor skills and neuronal regeneration in treated animals compared to controls, with the most pronounced effects observed when stimulation was initiated early after injury. These enhancements in neuroplasticity were reflected in improved ladder rung test scores and Basso, Beattie, and Bresnahan (BBB) scale results in DREADDs-treated rats. Histological analyses, including immunohistochemistry (IHC) staining, Western blotting, and quantitative reverse transcription PCR (qRT-PCR), confirmed that the treatment group exhibited a higher density of neurons, increased signaling protein expression, and reduced inflammatory markers. These findings suggest that chemogenetic stimulation, particularly when administered during the acute phase, effectively promotes neuroregeneration and motor recovery. Future research should focus on assessing the long-term safety and efficacy of chemogenetic virus injection and clozapine administration, with an emphasis on the timing of intervention.
{"title":"Effects of chemogenetic virus injection and clozapine administration in spinal cord injury","authors":"Ji Hyeon Kim , Sae Yeon Hwang , Hye-Lan Lee , Sol Lip Yoon , Yoon Ha , Hye Yeong Lee , Seungjun Ryu","doi":"10.1016/j.neurot.2025.e00547","DOIUrl":"10.1016/j.neurot.2025.e00547","url":null,"abstract":"<div><div>Neuromodulation therapy using chemogenetic stimulation has shown potential in enhancing motor recovery and neuroregeneration following spinal cord injury (SCI). These therapeutic benefits are hypothesized to result from the promotion of neuroplasticity, particularly when administered during the acute phase of injury. In this study, we investigated the effects of chemogenetic stimulation using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in conjunction with clozapine, a ligand for receptor activation. DREADDs enable targeted, reversible neuromodulation, facilitating the histological characterization of engineered neurons. We utilized these receptors to modulate G-protein-coupled receptor (GPCR) signaling pathways, leading to the activation or inhibition of intracellular signaling. The objective was to determine whether the administration of DREADDs and clozapine (0.1 mg/kg) could enhance motor function and neuronal recovery, particularly when applied during the acute phase of SCI. Weekly behavioral assessments demonstrated significant improvements in motor skills and neuronal regeneration in treated animals compared to controls, with the most pronounced effects observed when stimulation was initiated early after injury. These enhancements in neuroplasticity were reflected in improved ladder rung test scores and Basso, Beattie, and Bresnahan (BBB) scale results in DREADDs-treated rats. Histological analyses, including immunohistochemistry (IHC) staining, Western blotting, and quantitative reverse transcription PCR (qRT-PCR), confirmed that the treatment group exhibited a higher density of neurons, increased signaling protein expression, and reduced inflammatory markers. These findings suggest that chemogenetic stimulation, particularly when administered during the acute phase, effectively promotes neuroregeneration and motor recovery. Future research should focus on assessing the long-term safety and efficacy of chemogenetic virus injection and clozapine administration, with an emphasis on the timing of intervention.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"22 2","pages":"Article e00547"},"PeriodicalIF":5.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425740","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}
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