Ischemic stroke (IS) reduces the blood flow to the brain regions that trigger oxidative stress-induced biochemical, behavioural, molecular, and cellular impairments. Current treatment strategies are limited due to their narrow therapeutic window as, there is an urgent need to identify alternative therapeutic strategies in clinical settings to promote beneficial outcomes in stroke patients. Current study, focused on the neuro-protective potential of Arbutin (AR) in ischemic brain injury via modulation in Nrf-2/HO-1/HIF-1α/TFAM pathway. MCAO surgery was performed for 90 min, followed by reperfusion on male wistar rats, and the drug was administered intra-peritoneally. Animals were then sacrificed to estimate infarct volume, brain edema, BBB permeability, oxidative stress, inflammation, mitochondrial dysfunction, gene expression along with behavioural and morphological studies at different time intervals, i.e., 24 h and 21 days post-stroke. The results revealed that AR treatment improved neurological functions by maintaining BBB integrity and reducing edema, infarct volume, oxidative stress, and neuro-inflammation. It also improved the mitochondrial functions by increasing the gene expression of HIF-1α and TFAM along with reducing caspase-3 activation and iNOS gene expression through enhancing Nrf-2/HO-1 expression that supports the antioxidant activity of AR. Further, strong binding affinity of AR with the Nrf2 as revealed by the docking studies, reinforces our finding especially given the lack of prior target specific investigations exploring the detailed patho-mechanism of IS. Overall, AR exerts neuro-protective effect by modulating the Nrf-2/HO-1/HIF-1/TFAM pathways leading to improved mitochondrial functions, enhanced neurological outcomes, and increased neuronal survival which underscore its potential to as a therapeutic candidate for the treatment of IS.
{"title":"Modulation of Nrf-2/HO-1/HIF-1α/TFAM pathways by Arbutin in rat model of cerebral ischemic stroke.","authors":"Pinki Balhara, Sunil Sharma, Neeru Vasudeva, Neelam Rani, Sapna Grewal, Deepak Deepak, Babu Lal Jangir","doi":"10.1016/j.mcn.2025.104034","DOIUrl":"10.1016/j.mcn.2025.104034","url":null,"abstract":"<p><p>Ischemic stroke (IS) reduces the blood flow to the brain regions that trigger oxidative stress-induced biochemical, behavioural, molecular, and cellular impairments. Current treatment strategies are limited due to their narrow therapeutic window as, there is an urgent need to identify alternative therapeutic strategies in clinical settings to promote beneficial outcomes in stroke patients. Current study, focused on the neuro-protective potential of Arbutin (AR) in ischemic brain injury via modulation in Nrf-2/HO-1/HIF-1α/TFAM pathway. MCAO surgery was performed for 90 min, followed by reperfusion on male wistar rats, and the drug was administered intra-peritoneally. Animals were then sacrificed to estimate infarct volume, brain edema, BBB permeability, oxidative stress, inflammation, mitochondrial dysfunction, gene expression along with behavioural and morphological studies at different time intervals, i.e., 24 h and 21 days post-stroke. The results revealed that AR treatment improved neurological functions by maintaining BBB integrity and reducing edema, infarct volume, oxidative stress, and neuro-inflammation. It also improved the mitochondrial functions by increasing the gene expression of HIF-1α and TFAM along with reducing caspase-3 activation and iNOS gene expression through enhancing Nrf-2/HO-1 expression that supports the antioxidant activity of AR. Further, strong binding affinity of AR with the Nrf2 as revealed by the docking studies, reinforces our finding especially given the lack of prior target specific investigations exploring the detailed patho-mechanism of IS. Overall, AR exerts neuro-protective effect by modulating the Nrf-2/HO-1/HIF-1/TFAM pathways leading to improved mitochondrial functions, enhanced neurological outcomes, and increased neuronal survival which underscore its potential to as a therapeutic candidate for the treatment of IS.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104034"},"PeriodicalIF":2.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-01Epub Date: 2025-07-10DOI: 10.1016/j.mcn.2025.104030
Tae Jung Kim, Young-Ju Kim, Soo-Hyun Park, Youngjoon Kim, Sang-Bae Ko
Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.
{"title":"Neuroprotective effect of the peroxisome proliferator-activated receptor γ agonist lobeglitazone following intracerebral hemorrhage in rats.","authors":"Tae Jung Kim, Young-Ju Kim, Soo-Hyun Park, Youngjoon Kim, Sang-Bae Ko","doi":"10.1016/j.mcn.2025.104030","DOIUrl":"10.1016/j.mcn.2025.104030","url":null,"abstract":"<p><p>Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.</p>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":" ","pages":"104030"},"PeriodicalIF":2.4,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Traumatic brain injury is not constrained only to the brain but delayed secondary events disturb the end organ functioning via intense response of three homeostatic mechanisms such as sympathetic activity, inflammation, and immunosuppression. Current study involved weight drop model to induce TBI in Swiss albino mice. Eprosartan was administered orally after 30–45 min post injury to mice in 0.35 mg/kg and 0.7 mg/kg doses. Mice were tested for neurobehavioral alterations and multiple organs, including brain, heart, lungs, liver, and kidney were excised for further edema, biochemical, inflammatory, catecholamine, gene expression and histopathological estimations at both acute and chronic phases of injury. Results highlighted that Epro improved neurobehavioral performance, maintained the BBB and lung integrity. It also ameliorated the oxidative stress as well as docking studies exhibited strong binding affinity of Epro for HMGB1 and PDL-1, that further supported by low tissue HMGB1 and serum IL-6 and TNF-α cytokines levels which halted the systemic hyperinflammation. Moreover, Epro treatment successfully restored the cardiac, hepatic and kidney function through stabilized serum biomarkers with declined plasma noradrenaline levels that subsides the sympathetic storm. Considerably, a bizarre cellular morphology was displayed by the organs in acute phase of injury whereas Epro reversed the morphological changes at chronic stage. Also, epro encouraged the PD-1/PDL-1 and IL-10 gene expression in the tissues that regulates immune response. Thus, it is concluded that Epro exerts its organ protective effect against MODS via AT1/SNS pathway inhibition.
{"title":"Eprosartan alleviates the traumatic brain injury-induced multi-organ dysfunction syndrome in mice via AT1R/SNS/HMGB1 blockade and PDL-1 modulation","authors":"Manisha Thakur , Sunil Sharma , Neeru Vasudeva , Paras Saini , Deepika Lather , Deepak Deepak","doi":"10.1016/j.mcn.2025.104035","DOIUrl":"10.1016/j.mcn.2025.104035","url":null,"abstract":"<div><div>Traumatic brain injury is not constrained only to the brain but delayed secondary events disturb the end organ functioning via intense response of three homeostatic mechanisms such as sympathetic activity, inflammation, and immunosuppression. Current study involved weight drop model to induce TBI in Swiss albino mice. Eprosartan was administered orally after 30–45 min post injury to mice in 0.35 mg/kg and 0.7 mg/kg doses. Mice were tested for neurobehavioral alterations and multiple organs, including brain, heart, lungs, liver, and kidney were excised for further edema, biochemical, inflammatory, catecholamine, gene expression and histopathological estimations at both acute and chronic phases of injury. Results highlighted that Epro improved neurobehavioral performance, maintained the BBB and lung integrity. It also ameliorated the oxidative stress as well as docking studies exhibited strong binding affinity of Epro for HMGB1 and PDL-1, that further supported by low tissue HMGB1 and serum IL-6 and TNF-α cytokines levels which halted the systemic hyperinflammation. Moreover, Epro treatment successfully restored the cardiac, hepatic and kidney function through stabilized serum biomarkers with declined plasma noradrenaline levels that subsides the sympathetic storm. Considerably, a bizarre cellular morphology was displayed by the organs in acute phase of injury whereas Epro reversed the morphological changes at chronic stage. Also, epro encouraged the PD-1/PDL-1 and IL-10 gene expression in the tissues that regulates immune response. Thus, it is concluded that Epro exerts its organ protective effect against MODS via AT<sub>1</sub>/SNS pathway inhibition.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"135 ","pages":"Article 104035"},"PeriodicalIF":2.4,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144961403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.mcn.2025.104033
João Luís Vieira Monteiro de Barros , Caroline Amaral Machado , Ricardo Tadeu de Carvalho , Bruna da Silva Oliveira , Ingrid dos Santos Freitas , Lorena Taveira Nogueira , Giovana Cougo Ferreira , Heliana de Barros Fernandes , Brener Cunha Carvalho , Vivian Vasconcelos Costa , Antônio Lúcio Teixeira , Aline Silva de Miranda
Background
Indoleamine 2,3-dioxygenase (IDO) modulates the kynurenine pathway and may influence post-mild traumatic brain injury (mTBI) outcomes. This study tested whether IDO knockout (IDO-KO) mice exhibit distinct behavioral profiles and neurotrophic factor levels after a mTBI.
Methods
Male C57BL/6 WT and IDO-KO mice (10–12 weeks) underwent weight-drop-induced mTBI or sham procedures. Anxiety- and depression-like behaviors were assessed 72 h later via elevated plus maze and forced swim tests, respectively. Neurotrophic factors BDNF, NGF, NT3 and GDNF levels were measured by ELISA in the ipsilateral and contralateral prefrontal cortex and hippocampus.
Results
WT mice exhibited increased anxiety- and depressive-like behaviors post-mTBI, whereas IDO-KO mice did not show these behaviors. In parallel, mTBI increased BDNF levels in the ipsilateral hippocampus that were more pronounced in IDO-KO compared to WT. IDO-KO mice also exhibited a different pattern of NGF and GDNF compared to WT after mTBI.
Conclusion
IDO deficiency prevented mTBI-induced anxiety- and depressive-like behaviors and altered neurotrophic factor levels regionally. These findings implicate IDO in post-mTBI behavioral and neurotrophic responses, warranting further study of kynurenine pathway metabolites and downstream signaling to clarify the mechanism underlying the role of IDO in mTBI outcomes.
{"title":"Knockout of indoleamine 2,3-dioxygenase 1 gene expression improves depressive and anxiety-like phenotypes in a murine model of mild traumatic brain injury","authors":"João Luís Vieira Monteiro de Barros , Caroline Amaral Machado , Ricardo Tadeu de Carvalho , Bruna da Silva Oliveira , Ingrid dos Santos Freitas , Lorena Taveira Nogueira , Giovana Cougo Ferreira , Heliana de Barros Fernandes , Brener Cunha Carvalho , Vivian Vasconcelos Costa , Antônio Lúcio Teixeira , Aline Silva de Miranda","doi":"10.1016/j.mcn.2025.104033","DOIUrl":"10.1016/j.mcn.2025.104033","url":null,"abstract":"<div><h3>Background</h3><div>Indoleamine 2,3-dioxygenase (IDO) modulates the kynurenine pathway and may influence post-mild traumatic brain injury (mTBI) outcomes. This study tested whether IDO knockout (IDO-KO) mice exhibit distinct behavioral profiles and neurotrophic factor levels after a mTBI.</div></div><div><h3>Methods</h3><div>Male C57BL/6 WT and IDO-KO mice (10–12 weeks) underwent weight-drop-induced mTBI or sham procedures. Anxiety- and depression-like behaviors were assessed 72 h later via elevated plus maze and forced swim tests, respectively. Neurotrophic factors BDNF, NGF, NT3 and GDNF levels were measured by ELISA in the ipsilateral and contralateral prefrontal cortex and hippocampus.</div></div><div><h3>Results</h3><div>WT mice exhibited increased anxiety- and depressive-like behaviors post-mTBI, whereas IDO-KO mice did not show these behaviors. In parallel, mTBI increased BDNF levels in the ipsilateral hippocampus that were more pronounced in IDO-KO compared to WT. IDO-KO mice also exhibited a different pattern of NGF and GDNF compared to WT after mTBI.</div></div><div><h3>Conclusion</h3><div>IDO deficiency prevented mTBI-induced anxiety- and depressive-like behaviors and altered neurotrophic factor levels regionally. These findings implicate IDO in post-mTBI behavioral and neurotrophic responses, warranting further study of kynurenine pathway metabolites and downstream signaling to clarify the mechanism underlying the role of IDO in mTBI outcomes.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104033"},"PeriodicalIF":2.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-23DOI: 10.1016/j.mcn.2025.104031
Randy Bent Barker , Eda Karakaya , Didem Baran , Adviye Ergul , Kaan Yagmurlu , Mehmet Albayram , Onder Albayram
Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease marked by perivascular deposition of hyperphosphorylated tau (P-tau), is strongly linked to repetitive concussive traumatic brain injuries (TBIs). Emerging evidence implicates disruptions in the clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) from the brain—specifically within the glymphatic and meningeal lymphatic systems—as a pivotal driver of disease onset and progression. TBI disrupts glymphatic ISF–CSF exchange, compromising the clearance of pathogenic proteins—including P-tau, TDP-43, and inflammatory mediators—while promoting perivascular accumulation and neuroinflammation. Simultaneously, meningeal lymphatic dysfunction impedes CSF drainage and sustains neuroimmune activation, further amplifying glymphatic failure. Developmental trajectories of these systems suggest age-dependent susceptibilities to injury, potentially shaping both acute outcomes and long-term neurodegenerative risk. Species-specific differences between rodents and humans in brain fluid clearance pathways add translational complexity, emphasizing the need for refined models. This review reconceptualizes CTE as a disorder driven by disrupted brain fluid clearance, highlighting the convergent roles of glymphatic and meningeal lymphatic dysfunction in linking TBI to chronic neurodegeneration and identifying therapeutic targets to restore clearance and resilience.
{"title":"The glymphatic and meningeal lymphatic systems may converge, connecting traumatic brain injury progression with chronic traumatic encephalopathy onset","authors":"Randy Bent Barker , Eda Karakaya , Didem Baran , Adviye Ergul , Kaan Yagmurlu , Mehmet Albayram , Onder Albayram","doi":"10.1016/j.mcn.2025.104031","DOIUrl":"10.1016/j.mcn.2025.104031","url":null,"abstract":"<div><div>Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease marked by perivascular deposition of hyperphosphorylated tau (P-tau), is strongly linked to repetitive concussive traumatic brain injuries (TBIs). Emerging evidence implicates disruptions in the clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) from the brain—specifically within the glymphatic and meningeal lymphatic systems—as a pivotal driver of disease onset and progression. TBI disrupts glymphatic ISF–CSF exchange, compromising the clearance of pathogenic proteins—including P-tau, TDP-43, and inflammatory mediators—while promoting perivascular accumulation and neuroinflammation. Simultaneously, meningeal lymphatic dysfunction impedes CSF drainage and sustains neuroimmune activation, further amplifying glymphatic failure. Developmental trajectories of these systems suggest age-dependent susceptibilities to injury, potentially shaping both acute outcomes and long-term neurodegenerative risk. Species-specific differences between rodents and humans in brain fluid clearance pathways add translational complexity, emphasizing the need for refined models. This review reconceptualizes CTE as a disorder driven by disrupted brain fluid clearance, highlighting the convergent roles of glymphatic and meningeal lymphatic dysfunction in linking TBI to chronic neurodegeneration and identifying therapeutic targets to restore clearance and resilience.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104031"},"PeriodicalIF":2.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-22DOI: 10.1016/j.mcn.2025.104032
Kathleen M. Schoch , Dominic N. Nthenge-Ngumbau , Jennifer M. Brelsfoard , Gregory S. Hawk , Kathryn E. Saatman
Calpains are a family of calcium-dependent cysteine proteases that are activated within the brain minutes after a traumatic brain injury (TBI). Sustained calpain activation contributes to the secondary injury cascade of TBI and has been linked to neuronal and axonal degeneration and impairment of neurological function. Calpastatin is an endogenous protein encoded by the CAST gene which serves as a potent and highly selective inhibitor of calpains. This study investigates the potential of overexpressing human calpastatin (hCAST) via the ubiquitous prion protein promoter in a mouse model to alleviate TBI-induced brain damage and neurobehavioral dysfunction. Transgenic mice overexpressing hCAST and wildtype controls received a controlled cortical impact to induce contusive TBI or a sham injury. Overexpression of calpastatin significantly attenuated motor deficits over the first week in brain-injured mice. Visuospatial learning ability assessed in a Morris water maze on days 6 through 9 and novel object recognition on day 10 were impaired following TBI in wildtype mice. Both learning and memory function were improved in brain-injured hCAST overexpressing mice compared to wildtype mice. At 10 days post-injury brains were evaluated for cortical tissue damage and hippocampal neuron death. Analysis of Nissl-stained brain sections revealed no significant difference in the size of the cortical contusion between hCAST and wildtype animals. Similarly, hippocampal neurodegeneration associated with TBI was not modulated by hCAST overexpression. These findings demonstrate that inhibition of calpains aids in restoration of neurobehavioral function following TBI without protecting against cortical or hippocampal neuron death.
{"title":"Ubiquitous calpastatin overexpression in brain-injured mice attenuates motor and cognitive behavioral deficits without overt neuroprotection","authors":"Kathleen M. Schoch , Dominic N. Nthenge-Ngumbau , Jennifer M. Brelsfoard , Gregory S. Hawk , Kathryn E. Saatman","doi":"10.1016/j.mcn.2025.104032","DOIUrl":"10.1016/j.mcn.2025.104032","url":null,"abstract":"<div><div>Calpains are a family of calcium-dependent cysteine proteases that are activated within the brain minutes after a traumatic brain injury (TBI). Sustained calpain activation contributes to the secondary injury cascade of TBI and has been linked to neuronal and axonal degeneration and impairment of neurological function. Calpastatin is an endogenous protein encoded by the CAST gene which serves as a potent and highly selective inhibitor of calpains. This study investigates the potential of overexpressing human calpastatin (hCAST) <em>via</em> the ubiquitous prion protein promoter in a mouse model to alleviate TBI-induced brain damage and neurobehavioral dysfunction. Transgenic mice overexpressing hCAST and wildtype controls received a controlled cortical impact to induce contusive TBI or a sham injury. Overexpression of calpastatin significantly attenuated motor deficits over the first week in brain-injured mice. Visuospatial learning ability assessed in a Morris water maze on days 6 through 9 and novel object recognition on day 10 were impaired following TBI in wildtype mice. Both learning and memory function were improved in brain-injured hCAST overexpressing mice compared to wildtype mice. At 10 days post-injury brains were evaluated for cortical tissue damage and hippocampal neuron death. Analysis of Nissl-stained brain sections revealed no significant difference in the size of the cortical contusion between hCAST and wildtype animals. Similarly, hippocampal neurodegeneration associated with TBI was not modulated by hCAST overexpression. These findings demonstrate that inhibition of calpains aids in restoration of neurobehavioral function following TBI without protecting against cortical or hippocampal neuron death.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104032"},"PeriodicalIF":2.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144708171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-14DOI: 10.1016/j.mcn.2025.104029
Xiaoli Su , Xingli Tan , Ying Wang , Weiwei Liang , Di Wang , Di Huo , Hongyong Wang , Yan Qi , Wenmo Zhang , Ling Han , Dongmei Zhang , Ming Wang , Jing Xu , Honglin Feng
Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1G93A-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.
{"title":"DAPK1 induces motor neuron apoptosis in hSOD1G93A-linked amyotrophic lateral sclerosis via regulating the Xiap/JNK pathway","authors":"Xiaoli Su , Xingli Tan , Ying Wang , Weiwei Liang , Di Wang , Di Huo , Hongyong Wang , Yan Qi , Wenmo Zhang , Ling Han , Dongmei Zhang , Ming Wang , Jing Xu , Honglin Feng","doi":"10.1016/j.mcn.2025.104029","DOIUrl":"10.1016/j.mcn.2025.104029","url":null,"abstract":"<div><div>Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1<sup>G93A</sup>-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104029"},"PeriodicalIF":2.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autism Spectrum Disorder (ASD) exhibits a clear male bias, with males being approximately four times more likely to be affected than females. This difference has sparked curiosity about possible neurological elements that provide protection to females. One such neurological element that has shown promise is brain-derived neurotrophic factor (BDNF), essential for neuronal development, synaptic plasticity, and neuroprotection. ASD may be less common in females due to increased BDNF levels, which may be influenced by sex-specific epigenetic control and estrogen hormone. Research studies indicate that increased baseline BDNF in females promotes neurodevelopmental resilience and mitigates the environmental and genetic risk factors linked to ASD. Also, this protective impact may be enhanced by the regulatory function of estrogen in BDNF expression and the interaction of BDNF with X-linked genes. The processes by which BDNF contributes to sex differences are still not well understood despite strong evidence. Interpreting results is made more difficult by the variability of ASD symptoms and variations in study methodologies. In addition to that, it is yet unknown whether increased BDNF levels represent compensatory processes or actually provide protection. Longitudinal studies that monitor BDNF expression across developmental stages and look at sex-specific treatment approaches that target BDNF pathways should be the main focus of future research. Thus, a thorough understanding of how BDNF prevents sex differences in ASD may pave the way for innovative strategies destined to diminish the risk of ASD. In this milieu, this review explores the current research, highlighting the complex relationship between sex differences, BDNF, and the incidence of ASD.
{"title":"Sex-specific neuroprotection: Does BDNF shield girls from autism?","authors":"Takshashila Wankhade , Nayan Thakre , Manasi Tadas , Raj Katariya , Milind Umekar , Nandkishor Kotagale , Brijesh Taksande","doi":"10.1016/j.mcn.2025.104028","DOIUrl":"10.1016/j.mcn.2025.104028","url":null,"abstract":"<div><div>Autism Spectrum Disorder (ASD) exhibits a clear male bias, with males being approximately four times more likely to be affected than females. This difference has sparked curiosity about possible neurological elements that provide protection to females. One such neurological element that has shown promise is brain-derived neurotrophic factor (BDNF), essential for neuronal development, synaptic plasticity, and neuroprotection. ASD may be less common in females due to increased BDNF levels, which may be influenced by sex-specific epigenetic control and estrogen hormone. Research studies indicate that increased baseline BDNF in females promotes neurodevelopmental resilience and mitigates the environmental and genetic risk factors linked to ASD. Also, this protective impact may be enhanced by the regulatory function of estrogen in BDNF expression and the interaction of BDNF with X-linked genes. The processes by which BDNF contributes to sex differences are still not well understood despite strong evidence. Interpreting results is made more difficult by the variability of ASD symptoms and variations in study methodologies. In addition to that, it is yet unknown whether increased BDNF levels represent compensatory processes or actually provide protection. Longitudinal studies that monitor BDNF expression across developmental stages and look at sex-specific treatment approaches that target BDNF pathways should be the main focus of future research. Thus, a thorough understanding of how BDNF prevents sex differences in ASD may pave the way for innovative strategies destined to diminish the risk of ASD. In this milieu, this review explores the current research, highlighting the complex relationship between sex differences, BDNF, and the incidence of ASD.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104028"},"PeriodicalIF":2.4,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-17DOI: 10.1016/j.mcn.2025.104027
Katherine R. Hardin , Arjolyn B. Penas , Shuristeen Joubert , Changtian Ye , Kenneth R. Myers , James Q. Zheng
Actin-based cell motility drives many neurodevelopmental events including guided axonal growth. Fascin is a major family of F-actin bundling proteins, but its role in axon development in vivo and brain wiring remains unclear. Here, we report that fascin is required for axon development, brain wiring and function. We show that fascin is enriched in the motile filopodia of axonal growth cones and its inhibition impairs axonal extension and branching of hippocampal neurons in culture. We next provide evidence that fascin is essential for axon development and brain wiring in vivo using Drosophila melanogaster as a model. Drosophila expresses a single ortholog of mammalian fascin called Singed (Sn), which is expressed in the mushroom body (MB) of the central nervous system. Loss of Sn causes severe MB disruption, marked by α- and β-lobe defects indicative of altered axonal guidance. Sn-null flies also exhibit defective sensorimotor behaviors as assessed by the negative geotaxis assay. MB-specific expression of Sn in Sn-null flies rescues MB structure and sensorimotor deficits, indicating that Sn functions autonomously in MB neurons. Together, our data from primary neuronal culture and in vivo models highlight a critical role for fascin in brain development and function.
{"title":"A critical role for the fascin family of actin bundling proteins in axon development, brain wiring and function","authors":"Katherine R. Hardin , Arjolyn B. Penas , Shuristeen Joubert , Changtian Ye , Kenneth R. Myers , James Q. Zheng","doi":"10.1016/j.mcn.2025.104027","DOIUrl":"10.1016/j.mcn.2025.104027","url":null,"abstract":"<div><div>Actin-based cell motility drives many neurodevelopmental events including guided axonal growth. Fascin is a major family of F-actin bundling proteins, but its role in axon development <em>in vivo</em> and brain wiring remains unclear. Here, we report that fascin is required for axon development, brain wiring and function. We show that fascin is enriched in the motile filopodia of axonal growth cones and its inhibition impairs axonal extension and branching of hippocampal neurons in culture. We next provide evidence that fascin is essential for axon development and brain wiring <em>in vivo</em> using <em>Drosophila melanogaster</em> as a model. <em>Drosophila</em> expresses a single ortholog of mammalian fascin called Singed (Sn), which is expressed in the mushroom body (MB) of the central nervous system. Loss of Sn causes severe MB disruption, marked by α- and β-lobe defects indicative of altered axonal guidance. Sn-null flies also exhibit defective sensorimotor behaviors as assessed by the negative geotaxis assay. MB-specific expression of Sn in Sn-null flies rescues MB structure and sensorimotor deficits, indicating that Sn functions autonomously in MB neurons. Together, our data from primary neuronal culture and <em>in vivo</em> models highlight a critical role for fascin in brain development and function.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104027"},"PeriodicalIF":2.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-08DOI: 10.1016/j.mcn.2025.104024
Seanna E. Kelly , Rebecca Delventhal , Annika F. Barber
Traumatic brain injury is a significant public health problem, but the complex pathology of TBI has posed a barrier to a molecular understanding of the root causes of post-TBI sequelae. Fruit fly models of TBI offer opportunities to conduct high throughput screens for genes affecting multiple outcomes of TBI. This review provides a primer on fly traumatic injury paradigms, a summary of findings made in fly TBI models, and recommendations for future areas of TBI research amenable to the fly model. Using the whole-animal and head-specific TBI paradigms available in Drosophila, researchers have identified changes in acute mortality and median lifespan, reduction in locomotor function, immune activation, remodeling of metabolic functions and sleep, and acceleration of neurodegenerative phenotypes. Fly TBI models also show effects of age, diet, and sex on injury outcomes. Drosophila genetic tools offer unique advantages for high throughput screening, and fly screens have identified genes that affect acute mortality after injury. Further standardization of fly TBI paradigms will advance the field and allow discovery of genes and biochemical pathways that affect TBI outcomes across species and accelerate the development of evidence-based treatments for TBI survivors.
{"title":"Multiple models of TBI in Drosophila yield common and unique genetic, physiological, behavioral outcomes","authors":"Seanna E. Kelly , Rebecca Delventhal , Annika F. Barber","doi":"10.1016/j.mcn.2025.104024","DOIUrl":"10.1016/j.mcn.2025.104024","url":null,"abstract":"<div><div>Traumatic brain injury is a significant public health problem, but the complex pathology of TBI has posed a barrier to a molecular understanding of the root causes of post-TBI sequelae. Fruit fly models of TBI offer opportunities to conduct high throughput screens for genes affecting multiple outcomes of TBI. This review provides a primer on fly traumatic injury paradigms, a summary of findings made in fly TBI models, and recommendations for future areas of TBI research amenable to the fly model. Using the whole-animal and head-specific TBI paradigms available in Drosophila, researchers have identified changes in acute mortality and median lifespan, reduction in locomotor function, immune activation, remodeling of metabolic functions and sleep, and acceleration of neurodegenerative phenotypes. Fly TBI models also show effects of age, diet, and sex on injury outcomes. Drosophila genetic tools offer unique advantages for high throughput screening, and fly screens have identified genes that affect acute mortality after injury. Further standardization of fly TBI paradigms will advance the field and allow discovery of genes and biochemical pathways that affect TBI outcomes across species and accelerate the development of evidence-based treatments for TBI survivors.</div></div>","PeriodicalId":18739,"journal":{"name":"Molecular and Cellular Neuroscience","volume":"134 ","pages":"Article 104024"},"PeriodicalIF":2.6,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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