Mild traumatic brain injury(TBI), also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with ne...Mild traumatic brain injury(TBI), also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide(NO), the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha(HIF-1α), a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione(GSNO) and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.展开更多
Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipid...Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipids.Reactive aldehyde load causes redox alteration,neuroinflammation,neurodegeneration,pain-like behaviors,and locomotion deficits.Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions.In this study,we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDH2)to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI.N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1),a selective activator of ALDH2,was used as a therapeutic tool to suppress the 4-HNE load.SCI was induced by an impactor at the T9–10 vertebral level.Injured animals were initially treated with Alda-1 at 2 hours after injury,followed by once-daily treatment with Alda-1 for 30 consecutive days.Locomotor function was evaluated by the Basso Mouse Scale,and pain-like behaviors were assessed by mechanical allodynia and thermal algesia.ALDH2 activity was measured by enzymatic assay.4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry.SCI resulted in a sustained and prolonged overload of 4-HNE,which parallels with the decreased activity of ALDH2 and low functional recovery.Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI.Furthermore,the treatment with Alda-1 reduced neuroinflammation,oxidative stress,and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions.Conclusively,the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration,promotes the neurorepair process,and improves functional outcomes.Consequently,we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI.Animal procedures were approved by the Institutional Animal Care and Use Committee(IACUC)of MUSC(IACUC-2019-00864)on December 21,2019.展开更多
Contusion spinal cord injury(SCI)is a major medical and socio-economic problem globally.The incidence of SCI is highest among young adults due to motor vehicle accidents,military or sports injuries,and violence(Selvar...Contusion spinal cord injury(SCI)is a major medical and socio-economic problem globally.The incidence of SCI is highest among young adults due to motor vehicle accidents,military or sports injuries,and violence(Selvarajah et al.,2014).The elderly and children are also at risk due to falls and accidents.SCI causes neurodegeneration,with profound loss of locomotor and sensory functions(Siddiqui et al.,2015).Pain and depression are also prevalent in a majority of SCI patients.Expenses for severe SCI are high:initial hospitalization,rehabilitation,and most likely the continuing need for a caregiver and medical care.SCI survivors with less severe injuries usually face lower but still hefty medical bills.However,people≥50 years old with severe SCI may face medical expenses of over$1.8 million during their lifetimes.These injuries also affect spouses and family members,emotionally and financially,and most injuries jeopardize employment for those affected.展开更多
Asymmetric dimethylarginine(ADMA) and its enantiomer, symmetric dimethylarginine(SDMA), are naturally-occurring methylated metabolites of the L-arginine amino acid moiety of proteins followed by proteolysis(Grosse et ...Asymmetric dimethylarginine(ADMA) and its enantiomer, symmetric dimethylarginine(SDMA), are naturally-occurring methylated metabolites of the L-arginine amino acid moiety of proteins followed by proteolysis(Grosse et al., 2020). These metabolites were first identified in human urine in 1970.展开更多
Stroke ranks fourth among all causes of death and is the major cause of long-term disability in the United States.Furthermore,it is associated with significant morbidity/mortality and a direct/indirect cost of approxi...Stroke ranks fourth among all causes of death and is the major cause of long-term disability in the United States.Furthermore,it is associated with significant morbidity/mortality and a direct/indirect cost of approximately$65 billion annually(Roger et al.,2012).Other than thrombolysis by tissue plasminogen activator(t PA),which offers only a short window of treatment(-3–4 hours),展开更多
Lumbar spinal stenosis (LSS) causes ischemia, inflammation, demyelination and results in cauda equina (CE) syndrome, with pain and locomotor functional deficits. We investigated whether exogenous administration of S-n...Lumbar spinal stenosis (LSS) causes ischemia, inflammation, demyelination and results in cauda equina (CE) syndrome, with pain and locomotor functional deficits. We investigated whether exogenous administration of S-nitrosoglutathione (GSNO), an endogenous redox modulating anti-neuroinflammatory agent, hastens functional recovery in a CE compression (CEC) rat model. CEC was induced in adult female rats by the surgical implantation of two silicone blocks within the epidural spaces of L4-L6 vertebrae. GSNO (50 μg/kg body weight) was administered by gavage 1 h after the injury, and the treatment was continued daily thereafter. GSNO induced change in the pain threshold was evaluated for four days after the compression. Tissue analyses and locomotor function evaluation were carried out at two weeks and four weeks after the CEC respectively. GSNO significantly improved motor function in CEC rats as evidenced by an increased latency on rotarod compared with vehicle-treated CEC rats. CEC induced hyperalgesia was decreased by GSNO. GSNO also increased the expression of VEGF, reduced cellular infiltration (H&E staining) and apoptotic cell death (TUNEL assay), and hampered demyelination (LFB staining and g-ratio). These data demonstrate that administration of GSNO after CEC decreased inflammation, hyperalgesia and cell death leading to improved locomotor function of CEC rats. The therapeutic potential of GSNO observed in the present study with CEC rats suggests that GSNO is a candidate drug to test in LSS patients.展开更多
基金supported by grants from VA merit awards(BX3401 and RX2090)
文摘Mild traumatic brain injury(TBI), also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide(NO), the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha(HIF-1α), a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione(GSNO) and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.
基金supported by a grant from the State of South Carolina Spinal Cord Injury Research Fund Boardgrant No.SCIRF#2017(to MK)+2 种基金the NIH grant No.R21 NS114433(to JW and MK)supported by grants from the U.S.Department of Veterans Affairs,grant Nos.RX002090(IS)and BX003401(to AKS)The NIH Grants C06 RR018823 and No C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources also supported the animal work。
文摘Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipids.Reactive aldehyde load causes redox alteration,neuroinflammation,neurodegeneration,pain-like behaviors,and locomotion deficits.Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions.In this study,we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDH2)to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI.N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1),a selective activator of ALDH2,was used as a therapeutic tool to suppress the 4-HNE load.SCI was induced by an impactor at the T9–10 vertebral level.Injured animals were initially treated with Alda-1 at 2 hours after injury,followed by once-daily treatment with Alda-1 for 30 consecutive days.Locomotor function was evaluated by the Basso Mouse Scale,and pain-like behaviors were assessed by mechanical allodynia and thermal algesia.ALDH2 activity was measured by enzymatic assay.4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry.SCI resulted in a sustained and prolonged overload of 4-HNE,which parallels with the decreased activity of ALDH2 and low functional recovery.Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI.Furthermore,the treatment with Alda-1 reduced neuroinflammation,oxidative stress,and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions.Conclusively,the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration,promotes the neurorepair process,and improves functional outcomes.Consequently,we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI.Animal procedures were approved by the Institutional Animal Care and Use Committee(IACUC)of MUSC(IACUC-2019-00864)on December 21,2019.
基金supported by the grants from South Carolina Spinal Cord Injury Research Fund(No.CIRF2017 I-01)VA award(No.RX2090)
文摘Contusion spinal cord injury(SCI)is a major medical and socio-economic problem globally.The incidence of SCI is highest among young adults due to motor vehicle accidents,military or sports injuries,and violence(Selvarajah et al.,2014).The elderly and children are also at risk due to falls and accidents.SCI causes neurodegeneration,with profound loss of locomotor and sensory functions(Siddiqui et al.,2015).Pain and depression are also prevalent in a majority of SCI patients.Expenses for severe SCI are high:initial hospitalization,rehabilitation,and most likely the continuing need for a caregiver and medical care.SCI survivors with less severe injuries usually face lower but still hefty medical bills.However,people≥50 years old with severe SCI may face medical expenses of over$1.8 million during their lifetimes.These injuries also affect spouses and family members,emotionally and financially,and most injuries jeopardize employment for those affected.
基金supported by the State of South Carolina Spinal Cord Injury Research Fund Board grant No.SCIRF#2017(to MK)the NIH grant No.R21NS114433(to JW and MK)the U.S.Department of Veterans Affairs grant No.RX002090(to IS)。
文摘Asymmetric dimethylarginine(ADMA) and its enantiomer, symmetric dimethylarginine(SDMA), are naturally-occurring methylated metabolites of the L-arginine amino acid moiety of proteins followed by proteolysis(Grosse et al., 2020). These metabolites were first identified in human urine in 1970.
文摘Stroke ranks fourth among all causes of death and is the major cause of long-term disability in the United States.Furthermore,it is associated with significant morbidity/mortality and a direct/indirect cost of approximately$65 billion annually(Roger et al.,2012).Other than thrombolysis by tissue plasminogen activator(t PA),which offers only a short window of treatment(-3–4 hours),
文摘Lumbar spinal stenosis (LSS) causes ischemia, inflammation, demyelination and results in cauda equina (CE) syndrome, with pain and locomotor functional deficits. We investigated whether exogenous administration of S-nitrosoglutathione (GSNO), an endogenous redox modulating anti-neuroinflammatory agent, hastens functional recovery in a CE compression (CEC) rat model. CEC was induced in adult female rats by the surgical implantation of two silicone blocks within the epidural spaces of L4-L6 vertebrae. GSNO (50 μg/kg body weight) was administered by gavage 1 h after the injury, and the treatment was continued daily thereafter. GSNO induced change in the pain threshold was evaluated for four days after the compression. Tissue analyses and locomotor function evaluation were carried out at two weeks and four weeks after the CEC respectively. GSNO significantly improved motor function in CEC rats as evidenced by an increased latency on rotarod compared with vehicle-treated CEC rats. CEC induced hyperalgesia was decreased by GSNO. GSNO also increased the expression of VEGF, reduced cellular infiltration (H&E staining) and apoptotic cell death (TUNEL assay), and hampered demyelination (LFB staining and g-ratio). These data demonstrate that administration of GSNO after CEC decreased inflammation, hyperalgesia and cell death leading to improved locomotor function of CEC rats. The therapeutic potential of GSNO observed in the present study with CEC rats suggests that GSNO is a candidate drug to test in LSS patients.