Donald Stein - Academia.edu (original) (raw)

Papers by Donald Stein

Research paper thumbnail of Is a combination of progesterone and chloroquine more effective than either alone in the treatment of cerebral ischemic injury?

Restorative Neurology and Neuroscience, Mar 6, 2019

Research paper thumbnail of Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury

Journal of Neuroinflammation, Dec 1, 2015

Research paper thumbnail of Neurology: Pharmacological treatment of central nervous system injury

Research paper thumbnail of Morphological and Behavioral Characteristics of Embryonic Brain Tissue Transplants in Adult, Brain-damaged Subjects

Annals of the New York Academy of Sciences, Jun 1, 1987

Research paper thumbnail of Recombinant tissue plasminogen activator promotes, and progesterone attenuates, microglia/macrophage M1 polarization and recruitment of microglia after MCAO stroke in rats

Brain Behavior and Immunity, Oct 1, 2015

Tissue plasminogen activator (tPA) is one of the few approved treatments for stroke, but its effe... more Tissue plasminogen activator (tPA) is one of the few approved treatments for stroke, but its effects on the phenotype of microglia/macrophages are poorly understood. One of its side effects is an increase in the inflammatory response leading to neuronal cell damage and death in the ischemic cascade after stroke. Injury-induced activated microglia/macrophages can have dual functions as pro-inflammatory (M1) and anti-inflammatory (M2) factors in brain injury and repair. Recent studies show that progesterone (PROG) is a potent anti-inflammatory agent which affects microglia/macrophage expression after brain injury. We examined the interaction of tPA-induced expression of microglia/macrophage phenotypes and PROG's anti-inflammatory effects. tPA treatment increased the recruitment of microglia/macrophages, the polarity of M1 reactions, the expression of MIP-1α in neurons and capillaries, and the expression of MMP-3 compared to vehicle, and PROG modulated these effects. PROG treatment attenuates tPA-induced inflammatory alterations in brain capillaries and microglia/macrophages both in vivo and in vitro and thus may be a useful adjunct therapy when tPA is given for stroke.

Research paper thumbnail of Morphologic features of embryonic neocortex grafts in adult rats following frontal cortical ablation

Research paper thumbnail of Abstract TMP97: Progesterone Attenuates Acute Seizure and Brain Infarction by Modulating Pro-Inflammatory Cytokines in a Mouse Model of Neonatal Stroke

Stroke, Feb 1, 2013

Neonatal stroke is among the top ten causes of childhood death and causes long-term permanent dis... more Neonatal stroke is among the top ten causes of childhood death and causes long-term permanent disability and neurological deficits in survivors. In most cases, recurrent clonic seizure is the only clinical manifestation which worsens the stroke outcomes. A treatment or pediatric stroke is essential, but no candidate intervention is supported by substantiated data. We tested the hypothesis that progesterone (P4) treatment would be beneficial in a neonatal model of stroke. P12 CD1 mice (mixed gender) underwent permanent unilateral right common carotid ligation (pUCCL) or sham surgery (n=10/group). Pups which showed seizure activity during the 1h post-pUCCL were randomly assigned to receive P4 (8 mg/kg) or vehicle injections at 1, 3 and every 24h post-pUCCL for 6 days. We assessed acute behavioral seizures (during the first 4h post-pUCCL), serum pro-inflammatory cytokines (IL-1β, IL-6, TNFα at 6, 24 and 48h) and brain infarction (at day 7 by CV-staining). Cytokine data were analyzed by repeated measures one-way ANOVA followed by LSD and Tukey’s tests for independent comparisons. For seizure and infarct data, a two-tailed unpaired t-test was employed. We observed acute seizures during the first 4h post-pUCCL in the vehicle group (90.8±11.77). P4 treatment significantly ( P <0.05) reduced seizure occurrence (58.4±8.97) by 35% compared to vehicle. Repeated measures ANOVA revealed a significant group effect in IL-1β (F (2,15) =110.706; P <0.001), IL-6 (F (2,15 ) =66.067; P <0.001), and TNFα (F (2,15) =146.263; P <0.001) levels. Serum IL-1β, IL-6 and TNFα were significantly higher ( P <0.001) at 6 and 24h and remained elevated until 48h post-pUCCL in the vehicle group compared to sham. The P4-treated group showed a significant ( P <0.01) decrease in all pro-inflammatory cytokine levels at all time points. Further, pUCCL resulted in severe hemispheric damage (16.88±1.48) as evidenced by cresyl-violet staining at 7 days post-pUCCL. P4 treatment showed a significant ( P <0.05) reduction (4.93±1.1) in infarct volume (~70%) compared to vehicle. Our data demonstrate that P4 reduces acute seizures and brain infarction following neonatal stroke by modulating the inflammatory process, and warrants detailed studies of functional outcomes and mechanism of action.

Research paper thumbnail of Abstract WMP32: Immunomodulation and Neuroprotection by Progesterone in Infections following Ischemic Brain Injury in Middle-Aged Rats

Stroke, Feb 1, 2013

Infection is one of the major complications during the acute phase following stroke, accounting f... more Infection is one of the major complications during the acute phase following stroke, accounting for in-hospital deaths and worsening outcomes. We investigated the effect of delayed systemic inflammation on stroke outcomes and neuroprotection by progesterone (P4). Middle-aged rats underwent transient middle cerebral artery occlusion (MCAO) and received P4 (8 or 16 mg/kg) or vehicle until day 7 post-MCAO. Beginning 24h post-MCAO systemic inflammation was induced by 3 doses of lipopolysaccharide (LPS; 50 mg/kg, i.p.) to model post-stroke infections. We evaluated serum brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, brain infarctions, and conducted behavioral testing at multiple time points. Data were analyzed using repeated measures (RM)-ANOVA followed by LSD and Tukey’s tests. RM-ANOVA revealed a significant group effect ( F (4,25) =153.60; P <0.001) for IL-1β, IL-6 ( F (4,25) = 179.56; P <0.001), and TNFα ( F (4,25) = 58.94; P <0.001). Vehicle-alone showed a significant increase in all cytokine levels at different times following stroke which were further elevated after LPS injections in the vehicle+LPS group. P4 at both doses produced a significant decline ( P <0.05) in cytokine levels compared to vehicle and vehicle+LPS. BDNF levels showed a significant group effect ( F (4,25) = 24.838; P <0.001) and greater ( P <0.05) decrease in the vehicle+LPS group compared to vehicle-alone at 3 and 7 days post-injury. P4 significantly ( P <0.001) restored BDNF levels post-injury. At 3, 5 and 7 days, a significant group effect was observed in rotarod ( F (4, 26) = 33.059, P <0.001), grip strength ( F (4, 26) = 42.263, P <0.001), sensory neglect ( F (4, 26) = 150.712, P <0.001), and locomotor activity ( F (4,25) = 63.423, P <0.001). The vehicle group had significant ( P <0.05) deficits in all tests, and performance was worse in the vehicle+LPS group. P4 produced significant ( P <0.05) improvement in the animals’ performance on all tests. Systemic inflammation did not show an additive effect on infarct volume but P4 at both doses showed significant infarct reduction. Ourb data suggest that post-stroke infection exacerbates stroke outcomes and P4 exerts neuroprotective/modulatory effects through its anti-inflammatory and BDNF regulatory action.

Research paper thumbnail of Progesterone decreases cortical and sub-cortical edema in young and aged ovariectomized rats with brain injury

Restorative Neurology and Neuroscience, 2009

Research paper thumbnail of Bridging the translational divide: Emerging strategies in pharmacological approaches to traumatic brain injury

Neuropharmacology, Feb 1, 2019

Research paper thumbnail of Is Progesterone Worth Consideration as a Treatment for Brain Injury?

American Journal of Roentgenology, 2010

Research paper thumbnail of Progesterone attenuates thrombin-induced endothelial barrier disruption in the brain endothelial cell line bEnd.3: The role of tight junction proteins and the endothelial protein C receptor

Brain Research, Jul 1, 2015

Research paper thumbnail of Progesterone as a neuroprotective factor in traumatic and ischemic brain injury

Progress in Brain Research, 2009

The search for a "magic bullet&a... more The search for a "magic bullet" drug targeting a single receptor for the treatment of stroke or traumatic brain injury (TBI) has failed thus far for a variety of reasons. The pathophysiology of ischemic brain injury and TBI involves a number of mechanisms leading to neuronal injury, including excitotoxicity, free radical damage, inflammation, necrosis, and apoptosis. Brain injury also triggers auto-protective mechanisms, including the up-regulation of anti-inflammatory cytokines and endogenous antioxidants. In these conditions an agent with pleiotropic consequences is more likely to provide effective neuroprotection and repair than one operating primarily on a single, or a small number of, injury mechanisms. There is growing evidence, including recently published clinical trials, that progesterone and perhaps its metabolite allopregnanolone exert neuroprotective effects on the injured central nervous system (CNS). Laboratories around the world have shown that progesterone and allopregnanolone act through numerous metabolic and physiological pathways that can affect the injury response in many different tissues and organ systems. Furthermore, progesterone is a natural hormone, synthesized in both males and females, that can act as a pro-drug for other metabolites with their own distinct mode of action in CNS repair. These properties make progesterone a unique and compelling natural agent to consider for testing in clinical trial for CNS injuries including TBI and stroke.

Research paper thumbnail of Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

Brain Injury, Aug 14, 2015

Research paper thumbnail of Traumatic brain injury causes long-term reduction in serum Growth Hormone and persistent astrocytosis in the cortical-hypothalamo-pituitary axis of adult male rats

Journal of Neurotrauma, Mar 24, 2009

Research paper thumbnail of Traumatic Brain Injury Causes Long-Term Reduction in Serum Growth Hormone and Persistent Astrocytosis in the Cortico-Hypothalamo-Pituitary Axis of Adult Male Rats

Journal of Neurotrauma, Aug 1, 2009

Research paper thumbnail of Degeneration in the spinal cord of old rats

Experimental Neurology, Oct 1, 1980

... 00 wr 0 0 ax 0 zzada H 114 zar f'1 O d 184 MUFSON AND STEIN and lumbar levels. ... Pages... more ... 00 wr 0 0 ax 0 zzada H 114 zar f'1 O d 184 MUFSON AND STEIN and lumbar levels. ... Pages 217-251 in WJH NAUTA AND SOE EBBESSON, Eds., Contemporary Research Methods in Neuroanatomy. SpringerVerlag, New York. 6. ELIAS, MF 1978. ...

Research paper thumbnail of Combination Therapies for Traumatic Brain Injury: Prospective Considerations

Journal of Neurotrauma, Jun 1, 2009

Research paper thumbnail of The effects of training on passive avoidance deficits in rats with hippocampal lesions: A reply to Isaacson, Olton, Bauer, and Swart

Psychonomic science, 1967

Research paper thumbnail of Progesterone Treatment Attenuates Glycolytic Metabolism and Induces Senescence in Glioblastoma

Scientific Reports, 2019

We examined the effect of progesterone treatments on glycolytic metabolism and senescence as poss... more We examined the effect of progesterone treatments on glycolytic metabolism and senescence as possible mechanisms in controlling the growth of glioblastoma multiforme (GBM). In an orthotopic mouse model, after tumor establishment, athymic nude mice received treatment with progesterone or vehicle for 40 days. Compared to controls, high-dose progesterone administration produced a significant reduction in tumor size (~47%) and an increased survival rate (~43%) without any demonstrable toxicity to peripheral organs (liver, kidney). This was accompanied by a significant improvement in spontaneous locomotor activity and reduced anxiety-like behavior. In a follow-up in vitro study of U87MG-luc, U87dEGFR and U118MG tumor cells, we observed that high-dose progesterone inhibited expression of Glut1, which facilitated glucose transport into the cytoplasm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH; a glycolysis enzyme); ATP levels; and cytoplasmic FoxO1 and Phospho-FoxO1, both of which con...

Research paper thumbnail of Is a combination of progesterone and chloroquine more effective than either alone in the treatment of cerebral ischemic injury?

Restorative Neurology and Neuroscience, Mar 6, 2019

Research paper thumbnail of Progesterone treatment reduces neuroinflammation, oxidative stress and brain damage and improves long-term outcomes in a rat model of repeated mild traumatic brain injury

Journal of Neuroinflammation, Dec 1, 2015

Research paper thumbnail of Neurology: Pharmacological treatment of central nervous system injury

Research paper thumbnail of Morphological and Behavioral Characteristics of Embryonic Brain Tissue Transplants in Adult, Brain-damaged Subjects

Annals of the New York Academy of Sciences, Jun 1, 1987

Research paper thumbnail of Recombinant tissue plasminogen activator promotes, and progesterone attenuates, microglia/macrophage M1 polarization and recruitment of microglia after MCAO stroke in rats

Brain Behavior and Immunity, Oct 1, 2015

Tissue plasminogen activator (tPA) is one of the few approved treatments for stroke, but its effe... more Tissue plasminogen activator (tPA) is one of the few approved treatments for stroke, but its effects on the phenotype of microglia/macrophages are poorly understood. One of its side effects is an increase in the inflammatory response leading to neuronal cell damage and death in the ischemic cascade after stroke. Injury-induced activated microglia/macrophages can have dual functions as pro-inflammatory (M1) and anti-inflammatory (M2) factors in brain injury and repair. Recent studies show that progesterone (PROG) is a potent anti-inflammatory agent which affects microglia/macrophage expression after brain injury. We examined the interaction of tPA-induced expression of microglia/macrophage phenotypes and PROG's anti-inflammatory effects. tPA treatment increased the recruitment of microglia/macrophages, the polarity of M1 reactions, the expression of MIP-1α in neurons and capillaries, and the expression of MMP-3 compared to vehicle, and PROG modulated these effects. PROG treatment attenuates tPA-induced inflammatory alterations in brain capillaries and microglia/macrophages both in vivo and in vitro and thus may be a useful adjunct therapy when tPA is given for stroke.

Research paper thumbnail of Morphologic features of embryonic neocortex grafts in adult rats following frontal cortical ablation

Research paper thumbnail of Abstract TMP97: Progesterone Attenuates Acute Seizure and Brain Infarction by Modulating Pro-Inflammatory Cytokines in a Mouse Model of Neonatal Stroke

Stroke, Feb 1, 2013

Neonatal stroke is among the top ten causes of childhood death and causes long-term permanent dis... more Neonatal stroke is among the top ten causes of childhood death and causes long-term permanent disability and neurological deficits in survivors. In most cases, recurrent clonic seizure is the only clinical manifestation which worsens the stroke outcomes. A treatment or pediatric stroke is essential, but no candidate intervention is supported by substantiated data. We tested the hypothesis that progesterone (P4) treatment would be beneficial in a neonatal model of stroke. P12 CD1 mice (mixed gender) underwent permanent unilateral right common carotid ligation (pUCCL) or sham surgery (n=10/group). Pups which showed seizure activity during the 1h post-pUCCL were randomly assigned to receive P4 (8 mg/kg) or vehicle injections at 1, 3 and every 24h post-pUCCL for 6 days. We assessed acute behavioral seizures (during the first 4h post-pUCCL), serum pro-inflammatory cytokines (IL-1β, IL-6, TNFα at 6, 24 and 48h) and brain infarction (at day 7 by CV-staining). Cytokine data were analyzed by repeated measures one-way ANOVA followed by LSD and Tukey’s tests for independent comparisons. For seizure and infarct data, a two-tailed unpaired t-test was employed. We observed acute seizures during the first 4h post-pUCCL in the vehicle group (90.8±11.77). P4 treatment significantly ( P <0.05) reduced seizure occurrence (58.4±8.97) by 35% compared to vehicle. Repeated measures ANOVA revealed a significant group effect in IL-1β (F (2,15) =110.706; P <0.001), IL-6 (F (2,15 ) =66.067; P <0.001), and TNFα (F (2,15) =146.263; P <0.001) levels. Serum IL-1β, IL-6 and TNFα were significantly higher ( P <0.001) at 6 and 24h and remained elevated until 48h post-pUCCL in the vehicle group compared to sham. The P4-treated group showed a significant ( P <0.01) decrease in all pro-inflammatory cytokine levels at all time points. Further, pUCCL resulted in severe hemispheric damage (16.88±1.48) as evidenced by cresyl-violet staining at 7 days post-pUCCL. P4 treatment showed a significant ( P <0.05) reduction (4.93±1.1) in infarct volume (~70%) compared to vehicle. Our data demonstrate that P4 reduces acute seizures and brain infarction following neonatal stroke by modulating the inflammatory process, and warrants detailed studies of functional outcomes and mechanism of action.

Research paper thumbnail of Abstract WMP32: Immunomodulation and Neuroprotection by Progesterone in Infections following Ischemic Brain Injury in Middle-Aged Rats

Stroke, Feb 1, 2013

Infection is one of the major complications during the acute phase following stroke, accounting f... more Infection is one of the major complications during the acute phase following stroke, accounting for in-hospital deaths and worsening outcomes. We investigated the effect of delayed systemic inflammation on stroke outcomes and neuroprotection by progesterone (P4). Middle-aged rats underwent transient middle cerebral artery occlusion (MCAO) and received P4 (8 or 16 mg/kg) or vehicle until day 7 post-MCAO. Beginning 24h post-MCAO systemic inflammation was induced by 3 doses of lipopolysaccharide (LPS; 50 mg/kg, i.p.) to model post-stroke infections. We evaluated serum brain-derived neurotrophic factor (BDNF), pro-inflammatory cytokines, brain infarctions, and conducted behavioral testing at multiple time points. Data were analyzed using repeated measures (RM)-ANOVA followed by LSD and Tukey’s tests. RM-ANOVA revealed a significant group effect ( F (4,25) =153.60; P <0.001) for IL-1β, IL-6 ( F (4,25) = 179.56; P <0.001), and TNFα ( F (4,25) = 58.94; P <0.001). Vehicle-alone showed a significant increase in all cytokine levels at different times following stroke which were further elevated after LPS injections in the vehicle+LPS group. P4 at both doses produced a significant decline ( P <0.05) in cytokine levels compared to vehicle and vehicle+LPS. BDNF levels showed a significant group effect ( F (4,25) = 24.838; P <0.001) and greater ( P <0.05) decrease in the vehicle+LPS group compared to vehicle-alone at 3 and 7 days post-injury. P4 significantly ( P <0.001) restored BDNF levels post-injury. At 3, 5 and 7 days, a significant group effect was observed in rotarod ( F (4, 26) = 33.059, P <0.001), grip strength ( F (4, 26) = 42.263, P <0.001), sensory neglect ( F (4, 26) = 150.712, P <0.001), and locomotor activity ( F (4,25) = 63.423, P <0.001). The vehicle group had significant ( P <0.05) deficits in all tests, and performance was worse in the vehicle+LPS group. P4 produced significant ( P <0.05) improvement in the animals’ performance on all tests. Systemic inflammation did not show an additive effect on infarct volume but P4 at both doses showed significant infarct reduction. Ourb data suggest that post-stroke infection exacerbates stroke outcomes and P4 exerts neuroprotective/modulatory effects through its anti-inflammatory and BDNF regulatory action.

Research paper thumbnail of Progesterone decreases cortical and sub-cortical edema in young and aged ovariectomized rats with brain injury

Restorative Neurology and Neuroscience, 2009

Research paper thumbnail of Bridging the translational divide: Emerging strategies in pharmacological approaches to traumatic brain injury

Neuropharmacology, Feb 1, 2019

Research paper thumbnail of Is Progesterone Worth Consideration as a Treatment for Brain Injury?

American Journal of Roentgenology, 2010

Research paper thumbnail of Progesterone attenuates thrombin-induced endothelial barrier disruption in the brain endothelial cell line bEnd.3: The role of tight junction proteins and the endothelial protein C receptor

Brain Research, Jul 1, 2015

Research paper thumbnail of Progesterone as a neuroprotective factor in traumatic and ischemic brain injury

Progress in Brain Research, 2009

The search for a "magic bullet&a... more The search for a "magic bullet" drug targeting a single receptor for the treatment of stroke or traumatic brain injury (TBI) has failed thus far for a variety of reasons. The pathophysiology of ischemic brain injury and TBI involves a number of mechanisms leading to neuronal injury, including excitotoxicity, free radical damage, inflammation, necrosis, and apoptosis. Brain injury also triggers auto-protective mechanisms, including the up-regulation of anti-inflammatory cytokines and endogenous antioxidants. In these conditions an agent with pleiotropic consequences is more likely to provide effective neuroprotection and repair than one operating primarily on a single, or a small number of, injury mechanisms. There is growing evidence, including recently published clinical trials, that progesterone and perhaps its metabolite allopregnanolone exert neuroprotective effects on the injured central nervous system (CNS). Laboratories around the world have shown that progesterone and allopregnanolone act through numerous metabolic and physiological pathways that can affect the injury response in many different tissues and organ systems. Furthermore, progesterone is a natural hormone, synthesized in both males and females, that can act as a pro-drug for other metabolites with their own distinct mode of action in CNS repair. These properties make progesterone a unique and compelling natural agent to consider for testing in clinical trial for CNS injuries including TBI and stroke.

Research paper thumbnail of Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials

Brain Injury, Aug 14, 2015

Research paper thumbnail of Traumatic brain injury causes long-term reduction in serum Growth Hormone and persistent astrocytosis in the cortical-hypothalamo-pituitary axis of adult male rats

Journal of Neurotrauma, Mar 24, 2009

Research paper thumbnail of Traumatic Brain Injury Causes Long-Term Reduction in Serum Growth Hormone and Persistent Astrocytosis in the Cortico-Hypothalamo-Pituitary Axis of Adult Male Rats

Journal of Neurotrauma, Aug 1, 2009

Research paper thumbnail of Degeneration in the spinal cord of old rats

Experimental Neurology, Oct 1, 1980

... 00 wr 0 0 ax 0 zzada H 114 zar f'1 O d 184 MUFSON AND STEIN and lumbar levels. ... Pages... more ... 00 wr 0 0 ax 0 zzada H 114 zar f'1 O d 184 MUFSON AND STEIN and lumbar levels. ... Pages 217-251 in WJH NAUTA AND SOE EBBESSON, Eds., Contemporary Research Methods in Neuroanatomy. SpringerVerlag, New York. 6. ELIAS, MF 1978. ...

Research paper thumbnail of Combination Therapies for Traumatic Brain Injury: Prospective Considerations

Journal of Neurotrauma, Jun 1, 2009

Research paper thumbnail of The effects of training on passive avoidance deficits in rats with hippocampal lesions: A reply to Isaacson, Olton, Bauer, and Swart

Psychonomic science, 1967

Research paper thumbnail of Progesterone Treatment Attenuates Glycolytic Metabolism and Induces Senescence in Glioblastoma

Scientific Reports, 2019

We examined the effect of progesterone treatments on glycolytic metabolism and senescence as poss... more We examined the effect of progesterone treatments on glycolytic metabolism and senescence as possible mechanisms in controlling the growth of glioblastoma multiforme (GBM). In an orthotopic mouse model, after tumor establishment, athymic nude mice received treatment with progesterone or vehicle for 40 days. Compared to controls, high-dose progesterone administration produced a significant reduction in tumor size (~47%) and an increased survival rate (~43%) without any demonstrable toxicity to peripheral organs (liver, kidney). This was accompanied by a significant improvement in spontaneous locomotor activity and reduced anxiety-like behavior. In a follow-up in vitro study of U87MG-luc, U87dEGFR and U118MG tumor cells, we observed that high-dose progesterone inhibited expression of Glut1, which facilitated glucose transport into the cytoplasm; glyceraldehyde 3-phosphate dehydrogenase (GAPDH; a glycolysis enzyme); ATP levels; and cytoplasmic FoxO1 and Phospho-FoxO1, both of which con...