Medical Research and Surgery Services

Durham, NC, United States

Medical Research and Surgery Services

Durham, NC, United States
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Parihar V.K.,Medical Research and Surgery Services | Parihar V.K.,Duke University | Hattiangady B.,Medical Research and Surgery Services | Hattiangady B.,Duke University | And 6 more authors.
Molecular Psychiatry | Year: 2011

Maintenance of neurogenesis in adult hippocampus is important for functions such as mood and memory. As exposure to unpredictable chronic stress (UCS) results in decreased hippocampal neurogenesis, enhanced depressive- and anxiety-like behaviors, and memory dysfunction, it is believed that declined hippocampal neurogenesis mainly underlies the behavioral and cognitive abnormalities after UCS. However, the effects of predictable chronic mild stress (PCMS) such as the routine stress experienced in day-to-day life on functions such as mood, memory and hippocampal neurogenesis are unknown. Using FST and EPM tests on a prototype of adult rats, we demonstrate that PCMS (comprising 5 min of daily restraint stress for 28 days) decreases depressive- and anxiety-like behaviors for prolonged periods. Moreover, we illustrate that decreased depression and anxiety scores after PCMS are associated with ∼ 1.8-fold increase in the production and growth of new neurons in the hippocampus. Additionally, we found that PCMS leads to enhanced memory function in WMT as well as NORT. Collectively, these findings reveal that PCMS is beneficial to adult brain function, which is exemplified by increased hippocampal neurogenesis and improved mood and cognitive function. © 2011 Macmillan Publishers Limited All rights reserved.


Shetty A.K.,Medical Research and Surgery Services | Shetty A.K.,Duke University
Pharmacology and Therapeutics | Year: 2011

Resveratrol (RESV; 3,5,4′-tri-hydroxy stilbene), a naturally occurring phytoalexin, is found at a high concentration in the skin of red grapes and red wine. RESV mediates a wide-range of biological activities, which comprise an increased life span, anti-ischemic, anti-cancer, antiviral, anti-aging and anti-inflammatory properties. Studies in several animal prototypes of brain injury suggest that RESV is an effective neuroprotective compound. Ability to enter the brain after a peripheral administration and no adverse effects on the brain or body are other features that are appealing for using this compound as a therapy for brain injury or neurodegenerative diseases. The goal of this review is to discuss the promise of RESV for treating acute seizures, preventing the acute seizure or status epilepticus induced development of chronic epilepsy, and easing the chronic epilepsy typified by spontaneous recurrent seizures and cognitive dysfunction. First, the various beneficial effects of RESV on the normal brain are discussed to provide a rationale for considering RESV treatment in the management of acute seizures and epilepsy. Next, the detrimental effects of acute seizures or status epilepticus on the hippocampus and the implications of post-status epilepticus changes in the hippocampus towards the occurrence of chronic epilepsy and cognitive dysfunction are summarized. The final segment evaluates studies that have used RESV as a neuroprotective compound against seizures, and proposes studies that are critically needed prior to the clinical application of RESV as a prophylaxis against the development of chronic epilepsy and cognitive dysfunction after an episode of status epilepticus or head injury. © 2011 Elsevier Inc.


Waldau B.,Duke University | Waldau B.,Medical Research and Surgery Services | Hattiangady B.,Duke University | Hattiangady B.,Medical Research and Surgery Services | And 4 more authors.
Stem Cells | Year: 2010

Nearly 30% of patients with mesial temporal lobe epilepsy (TLE) are resistant to treatment with antiepileptic drugs. Neural stem cell (NSC) grafting into the hippocampus could offer an alternative therapy to hippocampal resection in these patients. As TLE is associated with reduced numbers of inhibitory gamma-amino butyric acid (GABA)-ergic interneurons and astrocytes expressing the anticonvulsant glial-derived neurotrophic factor (GDNF) in the hippocampus, we tested the hypothesis that grafting of NSCs that are capable of adding new GABA-ergic interneurons and GDNF-expressing astrocytes into the epileptic hippocampus restrains spontaneous recurrent motor seizures (SRMS) in chronic TLE. We grafted NSCs expanded in vitro from embryonic medial ganglionic eminence (MGE) into hippocampi of adult rats exhibiting chronic TLE with cognitive impairments. NSC grafting reduced frequencies of SRMS by 43% and stage V seizures by 90%. The duration of individual SRMS and the total time spent in seizures were reduced by 51 and 74%, respectively. Grafting did not improve the cognitive function however. Graft-derived cells (equivalent to ∼28% of injected cells) were observed in various layers of the epileptic hippocampus where they differentiated into NeuN+ neurons (13%), S-100β+ astrocytes (57%), and NG2+ oligodendrocyte-progenitors (3%). Furthermore, among graft-derived cells, 10% expressed GABA and 50% expressed GDNF. Additionally, NSC grafting restored GDNF in a vast majority of the hippocampal astrocytes but had no effect on neurogenesis. Thus, MGE-NSC therapy is efficacious for diminishing SRMS in chronic TLE. Addition of new GABA-ergic neurons and GDNF+ cells, and restoration of GDNF in the hippocampal astrocytes may underlie the therapeutic effect of MGE-NSC grafts. © AlphaMed Press.


Kuruba R.,Medical Research and Surgery Services | Kuruba R.,Duke University | Hattiangady B.,Medical Research and Surgery Services | Hattiangady B.,Texas A&M University | And 10 more authors.
PLoS ONE | Year: 2011

Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.


Hattiangady B.,Medical Research and Surgery Services | Hattiangady B.,Duke University | Kuruba R.,Medical Research and Surgery Services | Kuruba R.,Duke University | And 2 more authors.
Aging and Disease | Year: 2011

The aged population displays an enhanced risk for developing acute seizure (AS) activity. However, it is unclear whether AS activity in old age would result in a greater magnitude of hippocampal neurodegeneration and inflammation, and an increased predilection for developing chronic temporal lobe epilepsy (TLE) and cognitive dysfunction. Therefore, we addressed these issues in young-adult (5-months old) and aged (22-months old) F344 rats after three-hours of AS activity, induced through graded intraperitoneal injections of kainic acid (KA), and terminated through a diazepam injection. During the three-hours of AS activity, both young adult and aged groups exhibited similar numbers of stage-V motor seizures but the numbers of stage-IV motor seizures were greater in the aged group. In both age groups, three-hour AS activity induced degeneration of 50-55% of neurons in the dentate hilus, 22-32% of neurons in the granule cell layer and 49-52% neurons in the CA3 pyramidal cell layer without showing any interaction between the age and AS activity. However, degeneration of neurons in the CA1 pyramidal cell layer showed a clear interaction between the age and AS activity (12% in the young adult group and 56% in the aged group), suggesting that an advanced age makes the CA1 pyramidal neurons more susceptible to die with AS activity. The extent of inflammation measured through the numbers of activated microglial cells was similar between the two age groups. Interestingly, the predisposition for developing chronic TLE at 2-3 months after AS activity was 60% for young adult rats but 100% for aged rats. Moreover, both frequency & intensity of spontaneous recurrent seizures in the chronic phase after AS activity were 6-12 folds greater in aged rats than in young adult rats. Furthermore, aged rats lost their ability for spatial learning even in a scrupulous eleven-session water maze learning paradigm after AS activity, in divergence from young adult rats which retained the ability for spatial learning but had memory retrieval dysfunction after AS activity. Thus, AS activity in old age results in a greater loss of hippocampal CA1 pyramidal neurons, an increased propensity for developing robust chronic TLE, and a severe cognitive dysfunction.


Hattiangady B.,Texas A&M University | Hattiangady B.,Duke University | Hattiangady B.,Medical Research and Surgery Services | Shetty A.K.,Texas A&M University | And 3 more authors.
Current Protocols in Stem Cell Biology | Year: 2011

Neural stem cell (NSC) transplantation into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts ~30% of mesial temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), and induced pluripotent stem cells (iPSCs). However, to provide a comprehensive methodology involved in testing the efficacy of transplantation of NSCs in a rat model of chronic TLE, NSCs derived from the embryonic medial ganglionic eminence (MGE) are taken as an example in this unit. The topics comprise description of the required materials, reagents and equipment, and protocols for expanding MGE-NSCs in culture, generating chronically epileptic rats, the intrahippocampal grafting, post-grafting evaluation of the effects of NSC grafts on spontaneous recurrent seizures and cognitive impairments, analyses of the yield and the fate of graft-derived cells, and the effects of NSC grafts on the host hippocampus. © 2011 by John Wiley & Sons, Inc.


PubMed | Medical Research and Surgery Services
Type: Journal Article | Journal: Journal of cellular and molecular medicine | Year: 2010

Hippocampal inhibitory interneurons expressing glutamate decarboxylase-67 (GAD-67) considerably decline in number during old age. Studies in young adult animals further suggest that hippocampal GAD-67+ interneuron population is highly vulnerable to excitotoxic injury. However, the relative susceptibility of residual GAD-67+ interneurons in the aged hippocampus to excitotoxic injury is unknown. To elucidate this, using both adult and aged F344 rats, we performed stereological counting of GAD-67+ interneurons in different layers of the dentate gyrus and CA1 & CA3 sub-fields, at 3 months post-excitotoxic hippocampal injury inflicted through an intracerebroventricular administration of kainic acid (KA). Substantial reductions of GAD-67+ interneurons were found in all hippocampal layers and sub-fields after KA-induced injury in adult animals. Contrastingly, there was no significant change in GAD-67+ interneuron population in any of the hippocampal layers and sub-fields following similar injury in aged animals. Furthermore, the stability of GAD-67+ interneurons in aged rats after KA was not attributable to milder injury, as the overall extent of KA-induced hippocampal principal neuron loss was comparable between adult and aged rats. Interestingly, because of the age-related disparity in vulnerability of interneurons to injury, the surviving GAD-67+ interneuron population in the injured aged hippocampus remained comparable to that observed in the injured adult hippocampus despite enduring significant reductions in interneuron number with aging. Thus, unlike in the adult hippocampus, an excitotoxic injury to the aged hippocampus does not result in significantly decreased numbers of GAD-67+ interneurons. Persistence of GAD-67+ interneuron population in the injured aged hippocampus likely reflects an age-related change in the response of GAD-67+ interneurons to excitotoxic hippocampal injury. These results have implications towards understanding mechanisms underlying the evolution of initial precipitating injury into temporal lobe epilepsy in the elderly population.


PubMed | Medical Research and Surgery Services
Type: Journal Article | Journal: PloS one | Year: 2011

Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity.


PubMed | Medical Research and Surgery Services
Type: Journal Article | Journal: Hippocampus | Year: 2011

Increased neurogenesis in the dentate gyrus (DG) after brain insults such as excitotoxic lesions, seizures, or stroke is a well known phenomenon in the young hippocampus. This plasticity reflects an innate compensatory response of neural stem cells (NSCs) in the young hippocampus to preserve function or minimize damage after injury. However, injuries to the middle-aged and aged hippocampi elicit either no or dampened neurogenesis response, which could be due to an altered plasticity of NSCs and/or the hippocampus with age. We examined whether the plasticity of NSCs to increase neurogenesis in response to a milder injury such as partial deafferentation is preserved during aging. We quantified DG neurogenesis in the hippocampus of young, middle-aged, and aged F344 rats after partial deafferentation. A partial deafferentation of the left hippocampus without any apparent cell loss was induced via administration of Kainic acid (0.5 g in 1.0 l) into the right lateral ventricle of the brain. In this model, degeneration of CA3 pyramidal neurons and dentate hilar neurons in the right hippocampus results in loss of commissural axons which leads to partial deafferentation of the dendrites of dentate granule cells and CA1-CA3 pyramidal neurons in the left hippocampus. Quantification of newly born cells that are added to the dentate granule cell layer at postdeafferentation days 4-15 using 5-bromodeoxyuridine (BrdU) labeling revealed greatly increased addition of newly born cells (three fold increase) in the deafferented young and middle-aged hippocampi but not in the deafferented aged hippocampus. Measurement of newly born neurons using doublecortin (DCX) immunostaining also revealed similar findings. Analyses using BrdU-DCX dual immunofluorescence demonstrated no changes in neuronal fate-choice decision of newly born cells after deafferentation, in comparison to the age-matched naive hippocampus in all age groups. Thus, the plasticity of hippocampal NSCs to increase DG neurogenesis in response to a milder injury such as partial hippocampal deafferentation is preserved until middle age but lost at old age.


PubMed | Medical Research and Surgery Services
Type: Journal Article | Journal: Pharmacology & therapeutics | Year: 2011

Resveratrol (RESV; 3,5,4-tri-hydroxy stilbene), a naturally occurring phytoalexin, is found at a high concentration in the skin of red grapes and red wine. RESV mediates a wide-range of biological activities, which comprise an increased life span, anti-ischemic, anti-cancer, antiviral, anti-aging and anti-inflammatory properties. Studies in several animal prototypes of brain injury suggest that RESV is an effective neuroprotective compound. Ability to enter the brain after a peripheral administration and no adverse effects on the brain or body are other features that are appealing for using this compound as a therapy for brain injury or neurodegenerative diseases. The goal of this review is to discuss the promise of RESV for treating acute seizures, preventing the acute seizure or status epilepticus induced development of chronic epilepsy, and easing the chronic epilepsy typified by spontaneous recurrent seizures and cognitive dysfunction. First, the various beneficial effects of RESV on the normal brain are discussed to provide a rationale for considering RESV treatment in the management of acute seizures and epilepsy. Next, the detrimental effects of acute seizures or status epilepticus on the hippocampus and the implications of post-status epilepticus changes in the hippocampus towards the occurrence of chronic epilepsy and cognitive dysfunction are summarized. The final segment evaluates studies that have used RESV as a neuroprotective compound against seizures, and proposes studies that are critically needed prior to the clinical application of RESV as a prophylaxis against the development of chronic epilepsy and cognitive dysfunction after an episode of status epilepticus or head injury.

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