Regino Perez-polo - Profile on Academia.edu (original) (raw)
Papers by Regino Perez-polo
American Journal of Physiology-Heart and Circulatory Physiology, 2008
Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expressio... more Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS−/− and iNOS−/− mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-κB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS−/− and iNOS−/− mice received ATV (10 mg·kg−1·day−1; ATV+) or water alone (ATV−) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-κB in WT mice. It als...
Neurochemical Research, 2008
The examination of Bcl-2-associated X protein (Bax) protein's role in the activation of cognate n... more The examination of Bcl-2-associated X protein (Bax) protein's role in the activation of cognate nuclear, mitochondrial and ER cell death signaling cascades and the resulting effects on cell death phenotype in the brain after neonatal hypoxia-ischemia (HI) requires an understanding of neonatal HI insult and progression, as well as, its dysfunctional outcomes. In addition, knowledge of key concepts of oxidative stress, a major injurious component of HI, and the different cell death phenotypes (i.e. apoptosis and necrosis) will aid the design of appropriate useful experimental paradigms. Here we discuss organelle cell death signaling cascades in the context of the different cell death phenotypes associated with animal models of neonatal hypoxia ischemia and tissue culture models used in the study of hypoxia ischemia, focusing on the intracellular shifts of the Bcl-2 associated X protein (Bax) in the hypoxic brain.
Challenges in the Development of Rodent Models of Mild Traumatic Brain Injury
Journal of Neurotrauma, 2013
Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high ... more Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high frequency of mTBI, it is the least well studied. The prevalence of mTBI among service personnel returning from Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) and the recent reports of an association between repeated mTBI and the early onset of Alzheimer's and other types of dementias in retired athletes has focused much attention on mTBI. The study of mTBI requires the development and validation of experimental models and one of the most basic requirements for an experimental model is that it replicates important features of the injury or disease in humans. mTBI in humans is associated with acute symptoms such as loss of consciousness and pre- and/or posttraumatic amnesia. In addition, many mTBI patients experience long-term effects of mTBI, including deficits in speed of information processing, attention and concentration, memory acquisition, retention and retrieval, and reasoning and decision-making. Although methods for the diagnosis and evaluation of the acute and chronic effects of mTBI in humans are well established, the same is not the case for rodents, the most widely used animal for TBI studies. Despite the magnitude of the difficulties associated with adapting these methods for experimental mTBI research, they must be surmounted. The identification and testing of treatments for mTBI depends of the development, characterization and validation of reproducible, clinically relevant models of mTBI.
Special issue in honor of Jean de Vellis
Neurochemical Research, 2003
Role of Trophic Factors in Neuronal Aging
Advances in Experimental Medicine and Biology, 1989
Neuronal cell death is an event associated with the pathophysiology of nerve injury, stroke and a... more Neuronal cell death is an event associated with the pathophysiology of nerve injury, stroke and aging that is also a positive regulatory element in neuronal development. Whereas in all the aforementioned, the neurite outgrowth, as a part of the spectrum of responses by the surviving neurons, has been extensively studied at the molecular level; less is known about the molecular mechanisms that determine cell survival, except for the many classical biological experiments that have established that in vertebrate development, neuronal cell death is, in large measure but not uniquely, under the control of neuronotrophic factors such as the nerve growth factor protein, NGF (Thoenen et al., 1981). Two hypotheses have been proposed to explain the phenomena resulting in neuronal death. One hypothesis is that neurons are particularly susceptible to free radical damage because of their very low basal endogenous levels of antioxidants and antioxidant enzymes and that neuronotrophic factors acting through their respective cell surface receptors can shift the oxidant-antioxidant balance through induction of antioxidant enzymes (Perez-Polo et al., 1986). The second hypothesis proposes that there are “suicide genes” whose repression by NGF results in cell survival (Martin et al., 1988). Following axotomy to peripheral sympathetic and sensory neurons or the more central projections of the basal forebrain into the hippocampal areas, NGF has also been shown to be necessary to peripheral regeneration and to sparing effects on cholinergic basal forebrain neurons following deafferentation. NGF has dramatic trophic effects on cholinergic neurons of the CNS in vitro, a regeneration paradigm (Bostwick et al, 1987; Hatanaka et al, 1988). In aged rodent and human CNS and PNS, there are reported decreases in the levels of NGF and its receptor, NGFR (Goedert et al, 1986; Angelucci et al, 1988; Uchida and Tonionaga, 1987). In the periphery, NGF has well documented effects on certain neuronal and non-neuronal cells alike whose physiological relevance is not understood in a definitive fashion (Levi-Montalcini, 1987; Lillien and Claude, 1985; Thorpe, et al., 1988).
American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2002
The events occurring early in the burn wound trigger a sequence of local and systemic responses t... more The events occurring early in the burn wound trigger a sequence of local and systemic responses that influence cell and tissue survival and, consequently, wound healing and recovery. Using high-density oligonucleotide arrays we identified gene expression patterns in skin samples taken from a region of injury in the burn rat model. The associated genomic events include the differential expression of genes involved in cell survival and death, cell growth regulation, cell metabolism, inflammation, and immune response. The functional gene cluster detected and their time appearance matched the time sequence known to occur in burn wound healing.
International Journal of Developmental Neuroscience, 1996
In Vitro Model of Neuronal Aging and Development in the Nervous System
Model Systems of Development and Aging of the Nervous System, 1987
There is ample support for the hypothesis that free radical molecules play a major role in aging ... more There is ample support for the hypothesis that free radical molecules play a major role in aging (Harman, 1981; Pryor, 1984; Packer, 1984; Cutler, 1985). This is also true for the pathological changes associated with aging brain (Agranoff, 1984; Cutler, 1985) although the bulk of studies on free radical processes in the nervous system have focused on acute neural tissue injury (Demopoulos et al., 1979; Naftchi and Gennaro, 1985; Willmore et al., 1983; Chan et al., 1984; Anderson and Means, 1985; Anderson et al., 1985). Although the relative contributions of the different components of auto-oxidation events are not fully resolved at the chemical level [see Aust et al. (1985) and Halliwell and Gutteridge (1985) for two views], there is little doubt that lipid peroxidation events, irrespective of the sources of catalysis, and endogenous levels of “scavenging enzymes” are predictive of pathological consequences. Given the cellular heterogeneity and level of intercellular communication peculiar to the nervous system, there are advantages to the development and use of an in vitro system where pertinent variables can be controlled.
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2011
Debate: “Is Increasing Neuroinflammation Beneficial for Neural Repair?”
Journal of Neuroimmune Pharmacology, 2006
Page 1. INVITED REVIEW Debate: BIs Increasing Neuroinflammation Beneficial for Neural Repair?^ Ke... more Page 1. INVITED REVIEW Debate: BIs Increasing Neuroinflammation Beneficial for Neural Repair?^ Keith A. Crutcher & Howard E. Gendelman & Jonathan Kipnis & J. Regino Perez-Polo & VH Perry & Phillip G. Popovich & Lynne C. Weaver ...
Human neuroblastoma: Glial induced morphological differentiation
Neuroscience Letters, 1975
Rat C-6 glioma cells release a factor into culture medium which induces morphological differentia... more Rat C-6 glioma cells release a factor into culture medium which induces morphological differentiation in the IMR-32 human neuroblastoma cell line. The time course of differentiation and the effects on cell growth differ from those observed in mouse neuroblastoma cells. The effects of other cell lines and the relationship of differentiation to cell growth are discussed.
IL-1 Receptor Antagonist Prevents Apoptosis and Caspase-3 Activation after Spinal Cord Injury
Journal of Neurotrauma, 2001
One of the consequences of cytokine-orchestrated inflammation after CNS trauma is apoptosis. Our ... more One of the consequences of cytokine-orchestrated inflammation after CNS trauma is apoptosis. Our hypothesis is that cell death in the spinal cord after injury results in part from increased synthesis and release of IL-1beta. Using a ribonuclease protection assay, we demonstrated that there is increased transient expression of IL-1beta mRNA and, by using IL-1beta protein ELISA assay, that there are increased IL-1beta protein levels in the contused rat spinal cord, initially localized to the impact region of the spinal cord (segment T8). Using an ELISA cell death assay, we showed that there is apoptosis in the spinal cord 72 h after injury, a finding that was confirmed by measuring caspase-3 activity, which also significantly increased at the site of injury 72 h after trauma. Treatment of the contused spinal cord at the site of injury with the IL-1 receptor antagonist (rmIL-lra, 750 ng/mL) for 72 h using an osmotic minipump completely abolished the increases in contusion-induced apoptosis and caspase-3 activity.
Journal of Neuroscience Research, 1991
Dedication: Growth and trophic factors
Journal of Neuroscience Research, 1982
Introduction: Neuronotrophic factors
Journal of Neuroscience Research, 1982
Journal of Neuroscience Research, 2008
Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O 2 resuscitati... more Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O 2 resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl-2-associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle-associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle-specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase-3, and caspase-12. When HI-treated P7 rats were resuscitated with 100% O 2 (HHI), there were increased lesion volumes as determined by T2-weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic-cleaved interleukin-1β) and necrotic (increased nuclear 55-kDa-cleaved PARP-1 [poly-ADP-ribose 1] and decreased nuclear HMGB1 [nuclear high-mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O 2 resuscitation increases Bax-mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic-like cell death. In light of these findings, the use of 100% O 2 treatment for neonatal HI should bereevaluated.
Brain-derived neurotrophic factor (BDNF) protects cultured rat cerebellar granule neurons against glucose deprivation-induced apoptosis
Journal of Neural Transmission, 1998
In the present study, cell death induced by glucose deprivation in primary cultures of cerebellar... more In the present study, cell death induced by glucose deprivation in primary cultures of cerebellar granule neurons was examined. Glucose deprivation-induced apoptotic cell death was demonstrated using the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method and DNA fragmentation assays. When the effects of different neurotrophins on the survival of cerebellar granule neurons after glucose deprivation were assessed, BDNF, but not NT-3 or NGF, was found to protect cerebellar granule neurons against glucose deprivation-induced cell death. In addition, BDNF treatment increased c-Fos immunoreactivity in the cerebellar granule neurons. These results are consistent with the hypothesis that neuronal death due to glucose deprivation has a significant apoptotic component and that neurotrophins can protect against hypoglycemic damage.
The Journal of Immunology, 2008
Antiapoptotic therapies in the treatment of spinal cord injury
Future Neurology, 2007
Mechanical trauma to the spinal cord triggers events resulting in the death of neurons and glia o... more Mechanical trauma to the spinal cord triggers events resulting in the death of neurons and glia over several weeks following the initial injury. It has been suggested that the prevention of delayed apoptosis after spinal cord injury (SCI) is likely to have a beneficial effect by reducing the extent of neuronal and oligodendroglial death, which would translate into better functional outcomes. Drugs acting at different levels in the apoptotic cascade (i.e., caspase inhibitors and antiapoptotic Bcl-xL) have been shown to decrease apoptotic cell death, but benefits in functional outcomes result only when inflammation is also decreased. Furthermore, long-term antiapoptotic therapy can result in nonapoptotic death with necrotic features, which will further increase inflammation and worsen outcome. Even though neuroprotective therapies are one of the targets for the promotion of functional recovery after SCI, targeting only post-SCI apoptosis is unlikely to be as successful as more integrated interventions that ...
Cardiovascular Research, 2010
Time for primary review: 26 days Aims MicroRNAs (miRNAs) regulate various cardiac processes inclu... more Time for primary review: 26 days Aims MicroRNAs (miRNAs) regulate various cardiac processes including cell proliferation and apoptosis. Pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)-g agonist, protects against myocardial ischaemiareperfusion (IR) injury. We assessed the effects of PPAR-g activation on myocardial miRNA levels and the role of miRNAs in IR injury. Methods and results We evaluated the expression changes of miRNAs in the rat heart after PIO administration using miRNA arrays and then confirmed the result by northern blot. miR-29a and c levels decreased remarkably after 7-day treatment with PIO. In H9c2 cells, the effects of PIO and rosiglitazone on miR-29 expression levels were blocked by a selective PPAR-g inhibitor GW9662. Downregulation of miR-29 by antisense inhibitor or by PIO protected H9c2 cells from simulated IR injury, indicated as increased cell survival and decreased caspase-3 activity. In contrast, overexpressing miR-29 promoted apoptosis and completely blocked the protective effect of PIO. Antagomirs against miR-29a or-29c significantly reduced myocardial infarct size and apoptosis in hearts subjected to IR injury. Western blot analyses demonstrated that Mcl-2, an anti-apoptotic Bcl-2 family member, was increased by miR-29 inhibition. Conclusion Downregulation of miR-29 protected hearts against IR injury. The modulation of miRNAs can be achieved by pharmacological intervention. These findings provide a rationale for the development of miRNA-based strategies for the attenuation of IR injury.
American Journal of Physiology-Heart and Circulatory Physiology, 2008
Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expressio... more Pretreatment with atorvastatin (ATV) reduces infarct size (IS) and increases myocardial expression of phosphorylated endothelial nitric oxide synthase (p-eNOS), inducible NOS (iNOS), and cyclooxygenase-2 (COX2) in the rat. Inhibiting COX2 abolished the ATV-induced IS limitation without affecting p-eNOS and iNOS expression. We investigated 1) whether 3-day ATV pretreatment limits IS in eNOS−/− and iNOS−/− mice and 2) whether COX2 expression and/or activation by ATV is eNOS, iNOS, and/or NF-κB dependent. Male C57BL/6 wild-type (WT), University of North Carolina eNOS−/− and iNOS−/− mice received ATV (10 mg·kg−1·day−1; ATV+) or water alone (ATV−) for 3 days. Mice underwent 30 min of coronary artery occlusion and 4 h of reperfusion, or hearts were harvested and subjected to ELISA, immunoblotting, biotin switch, and electrophoretic mobility shift assay. As a result, ATV reduced IS only in the WT mice. ATV increased eNOS, p-eNOS, iNOS, and COX2 levels and activated NF-κB in WT mice. It als...
Neurochemical Research, 2008
The examination of Bcl-2-associated X protein (Bax) protein's role in the activation of cognate n... more The examination of Bcl-2-associated X protein (Bax) protein's role in the activation of cognate nuclear, mitochondrial and ER cell death signaling cascades and the resulting effects on cell death phenotype in the brain after neonatal hypoxia-ischemia (HI) requires an understanding of neonatal HI insult and progression, as well as, its dysfunctional outcomes. In addition, knowledge of key concepts of oxidative stress, a major injurious component of HI, and the different cell death phenotypes (i.e. apoptosis and necrosis) will aid the design of appropriate useful experimental paradigms. Here we discuss organelle cell death signaling cascades in the context of the different cell death phenotypes associated with animal models of neonatal hypoxia ischemia and tissue culture models used in the study of hypoxia ischemia, focusing on the intracellular shifts of the Bcl-2 associated X protein (Bax) in the hypoxic brain.
Challenges in the Development of Rodent Models of Mild Traumatic Brain Injury
Journal of Neurotrauma, 2013
Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high ... more Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high frequency of mTBI, it is the least well studied. The prevalence of mTBI among service personnel returning from Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) and the recent reports of an association between repeated mTBI and the early onset of Alzheimer's and other types of dementias in retired athletes has focused much attention on mTBI. The study of mTBI requires the development and validation of experimental models and one of the most basic requirements for an experimental model is that it replicates important features of the injury or disease in humans. mTBI in humans is associated with acute symptoms such as loss of consciousness and pre- and/or posttraumatic amnesia. In addition, many mTBI patients experience long-term effects of mTBI, including deficits in speed of information processing, attention and concentration, memory acquisition, retention and retrieval, and reasoning and decision-making. Although methods for the diagnosis and evaluation of the acute and chronic effects of mTBI in humans are well established, the same is not the case for rodents, the most widely used animal for TBI studies. Despite the magnitude of the difficulties associated with adapting these methods for experimental mTBI research, they must be surmounted. The identification and testing of treatments for mTBI depends of the development, characterization and validation of reproducible, clinically relevant models of mTBI.
Special issue in honor of Jean de Vellis
Neurochemical Research, 2003
Role of Trophic Factors in Neuronal Aging
Advances in Experimental Medicine and Biology, 1989
Neuronal cell death is an event associated with the pathophysiology of nerve injury, stroke and a... more Neuronal cell death is an event associated with the pathophysiology of nerve injury, stroke and aging that is also a positive regulatory element in neuronal development. Whereas in all the aforementioned, the neurite outgrowth, as a part of the spectrum of responses by the surviving neurons, has been extensively studied at the molecular level; less is known about the molecular mechanisms that determine cell survival, except for the many classical biological experiments that have established that in vertebrate development, neuronal cell death is, in large measure but not uniquely, under the control of neuronotrophic factors such as the nerve growth factor protein, NGF (Thoenen et al., 1981). Two hypotheses have been proposed to explain the phenomena resulting in neuronal death. One hypothesis is that neurons are particularly susceptible to free radical damage because of their very low basal endogenous levels of antioxidants and antioxidant enzymes and that neuronotrophic factors acting through their respective cell surface receptors can shift the oxidant-antioxidant balance through induction of antioxidant enzymes (Perez-Polo et al., 1986). The second hypothesis proposes that there are “suicide genes” whose repression by NGF results in cell survival (Martin et al., 1988). Following axotomy to peripheral sympathetic and sensory neurons or the more central projections of the basal forebrain into the hippocampal areas, NGF has also been shown to be necessary to peripheral regeneration and to sparing effects on cholinergic basal forebrain neurons following deafferentation. NGF has dramatic trophic effects on cholinergic neurons of the CNS in vitro, a regeneration paradigm (Bostwick et al, 1987; Hatanaka et al, 1988). In aged rodent and human CNS and PNS, there are reported decreases in the levels of NGF and its receptor, NGFR (Goedert et al, 1986; Angelucci et al, 1988; Uchida and Tonionaga, 1987). In the periphery, NGF has well documented effects on certain neuronal and non-neuronal cells alike whose physiological relevance is not understood in a definitive fashion (Levi-Montalcini, 1987; Lillien and Claude, 1985; Thorpe, et al., 1988).
American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2002
The events occurring early in the burn wound trigger a sequence of local and systemic responses t... more The events occurring early in the burn wound trigger a sequence of local and systemic responses that influence cell and tissue survival and, consequently, wound healing and recovery. Using high-density oligonucleotide arrays we identified gene expression patterns in skin samples taken from a region of injury in the burn rat model. The associated genomic events include the differential expression of genes involved in cell survival and death, cell growth regulation, cell metabolism, inflammation, and immune response. The functional gene cluster detected and their time appearance matched the time sequence known to occur in burn wound healing.
International Journal of Developmental Neuroscience, 1996
In Vitro Model of Neuronal Aging and Development in the Nervous System
Model Systems of Development and Aging of the Nervous System, 1987
There is ample support for the hypothesis that free radical molecules play a major role in aging ... more There is ample support for the hypothesis that free radical molecules play a major role in aging (Harman, 1981; Pryor, 1984; Packer, 1984; Cutler, 1985). This is also true for the pathological changes associated with aging brain (Agranoff, 1984; Cutler, 1985) although the bulk of studies on free radical processes in the nervous system have focused on acute neural tissue injury (Demopoulos et al., 1979; Naftchi and Gennaro, 1985; Willmore et al., 1983; Chan et al., 1984; Anderson and Means, 1985; Anderson et al., 1985). Although the relative contributions of the different components of auto-oxidation events are not fully resolved at the chemical level [see Aust et al. (1985) and Halliwell and Gutteridge (1985) for two views], there is little doubt that lipid peroxidation events, irrespective of the sources of catalysis, and endogenous levels of “scavenging enzymes” are predictive of pathological consequences. Given the cellular heterogeneity and level of intercellular communication peculiar to the nervous system, there are advantages to the development and use of an in vitro system where pertinent variables can be controlled.
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience, 2011
Debate: “Is Increasing Neuroinflammation Beneficial for Neural Repair?”
Journal of Neuroimmune Pharmacology, 2006
Page 1. INVITED REVIEW Debate: BIs Increasing Neuroinflammation Beneficial for Neural Repair?^ Ke... more Page 1. INVITED REVIEW Debate: BIs Increasing Neuroinflammation Beneficial for Neural Repair?^ Keith A. Crutcher & Howard E. Gendelman & Jonathan Kipnis & J. Regino Perez-Polo & VH Perry & Phillip G. Popovich & Lynne C. Weaver ...
Human neuroblastoma: Glial induced morphological differentiation
Neuroscience Letters, 1975
Rat C-6 glioma cells release a factor into culture medium which induces morphological differentia... more Rat C-6 glioma cells release a factor into culture medium which induces morphological differentiation in the IMR-32 human neuroblastoma cell line. The time course of differentiation and the effects on cell growth differ from those observed in mouse neuroblastoma cells. The effects of other cell lines and the relationship of differentiation to cell growth are discussed.
IL-1 Receptor Antagonist Prevents Apoptosis and Caspase-3 Activation after Spinal Cord Injury
Journal of Neurotrauma, 2001
One of the consequences of cytokine-orchestrated inflammation after CNS trauma is apoptosis. Our ... more One of the consequences of cytokine-orchestrated inflammation after CNS trauma is apoptosis. Our hypothesis is that cell death in the spinal cord after injury results in part from increased synthesis and release of IL-1beta. Using a ribonuclease protection assay, we demonstrated that there is increased transient expression of IL-1beta mRNA and, by using IL-1beta protein ELISA assay, that there are increased IL-1beta protein levels in the contused rat spinal cord, initially localized to the impact region of the spinal cord (segment T8). Using an ELISA cell death assay, we showed that there is apoptosis in the spinal cord 72 h after injury, a finding that was confirmed by measuring caspase-3 activity, which also significantly increased at the site of injury 72 h after trauma. Treatment of the contused spinal cord at the site of injury with the IL-1 receptor antagonist (rmIL-lra, 750 ng/mL) for 72 h using an osmotic minipump completely abolished the increases in contusion-induced apoptosis and caspase-3 activity.
Journal of Neuroscience Research, 1991
Dedication: Growth and trophic factors
Journal of Neuroscience Research, 1982
Introduction: Neuronotrophic factors
Journal of Neuroscience Research, 1982
Journal of Neuroscience Research, 2008
Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O 2 resuscitati... more Perinatal hypoxia-ischemia (HI) occurs in 0.2%-0.4% of all live births, with 100% O 2 resuscitation (HHI) remaining a standard clinical treatment. HI produces a broad spectrum of neuronal death phenotypes ranging from a more noninflammatory apoptotic death to a more inflammatory necrotic cell death that may be responsible for the broad spectrum of reported dysfunctional outcomes. However, the mechanisms that would account for this phenotypic spectrum of cell death are not fully understood. Here, we provide evidence that Bcl-2-associated X protein (Bax) can shuttle to different subcellular compartments in response to HI, thus triggering the different organelle-associated cell death signaling cascades resulting in cell death phenotype diversity. There was an early increase in intranuclear and total nuclear Bax protein levels followed by a later Bax redistribution to the mitochondria and endoplasmic reticulum (ER). Associated with the organelle-specific Bax shuttling time course, there was an increase in nuclear phosphorylated p53, cytosolic cleaved caspase-3, and caspase-12. When HI-treated P7 rats were resuscitated with 100% O 2 (HHI), there were increased lesion volumes as determined by T2-weighted magnetic resonance imaging with no change in cortical apoptotic signaling compared with HI treatment alone. There was, however, increased inflammatory (cytosolic-cleaved interleukin-1β) and necrotic (increased nuclear 55-kDa-cleaved PARP-1 [poly-ADP-ribose 1] and decreased nuclear HMGB1 [nuclear high-mobility group box 1]) after HHI. Furthermore, HHI increased ER calpain activation and ER Bax protein levels compared with HI alone. These data suggest that 100% O 2 resuscitation increases Bax-mediated activation of ER cell death signaling, inflammation, and lesion volume by increasing necrotic-like cell death. In light of these findings, the use of 100% O 2 treatment for neonatal HI should bereevaluated.
Brain-derived neurotrophic factor (BDNF) protects cultured rat cerebellar granule neurons against glucose deprivation-induced apoptosis
Journal of Neural Transmission, 1998
In the present study, cell death induced by glucose deprivation in primary cultures of cerebellar... more In the present study, cell death induced by glucose deprivation in primary cultures of cerebellar granule neurons was examined. Glucose deprivation-induced apoptotic cell death was demonstrated using the terminal transferase-mediated (TdT) deoxyuridine triphosphate (d-UTP)-biotin nick end labeling (TUNEL) method and DNA fragmentation assays. When the effects of different neurotrophins on the survival of cerebellar granule neurons after glucose deprivation were assessed, BDNF, but not NT-3 or NGF, was found to protect cerebellar granule neurons against glucose deprivation-induced cell death. In addition, BDNF treatment increased c-Fos immunoreactivity in the cerebellar granule neurons. These results are consistent with the hypothesis that neuronal death due to glucose deprivation has a significant apoptotic component and that neurotrophins can protect against hypoglycemic damage.
The Journal of Immunology, 2008
Antiapoptotic therapies in the treatment of spinal cord injury
Future Neurology, 2007
Mechanical trauma to the spinal cord triggers events resulting in the death of neurons and glia o... more Mechanical trauma to the spinal cord triggers events resulting in the death of neurons and glia over several weeks following the initial injury. It has been suggested that the prevention of delayed apoptosis after spinal cord injury (SCI) is likely to have a beneficial effect by reducing the extent of neuronal and oligodendroglial death, which would translate into better functional outcomes. Drugs acting at different levels in the apoptotic cascade (i.e., caspase inhibitors and antiapoptotic Bcl-xL) have been shown to decrease apoptotic cell death, but benefits in functional outcomes result only when inflammation is also decreased. Furthermore, long-term antiapoptotic therapy can result in nonapoptotic death with necrotic features, which will further increase inflammation and worsen outcome. Even though neuroprotective therapies are one of the targets for the promotion of functional recovery after SCI, targeting only post-SCI apoptosis is unlikely to be as successful as more integrated interventions that ...
Cardiovascular Research, 2010
Time for primary review: 26 days Aims MicroRNAs (miRNAs) regulate various cardiac processes inclu... more Time for primary review: 26 days Aims MicroRNAs (miRNAs) regulate various cardiac processes including cell proliferation and apoptosis. Pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)-g agonist, protects against myocardial ischaemiareperfusion (IR) injury. We assessed the effects of PPAR-g activation on myocardial miRNA levels and the role of miRNAs in IR injury. Methods and results We evaluated the expression changes of miRNAs in the rat heart after PIO administration using miRNA arrays and then confirmed the result by northern blot. miR-29a and c levels decreased remarkably after 7-day treatment with PIO. In H9c2 cells, the effects of PIO and rosiglitazone on miR-29 expression levels were blocked by a selective PPAR-g inhibitor GW9662. Downregulation of miR-29 by antisense inhibitor or by PIO protected H9c2 cells from simulated IR injury, indicated as increased cell survival and decreased caspase-3 activity. In contrast, overexpressing miR-29 promoted apoptosis and completely blocked the protective effect of PIO. Antagomirs against miR-29a or-29c significantly reduced myocardial infarct size and apoptosis in hearts subjected to IR injury. Western blot analyses demonstrated that Mcl-2, an anti-apoptotic Bcl-2 family member, was increased by miR-29 inhibition. Conclusion Downregulation of miR-29 protected hearts against IR injury. The modulation of miRNAs can be achieved by pharmacological intervention. These findings provide a rationale for the development of miRNA-based strategies for the attenuation of IR injury.