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1.  Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling 
Brain research  2012;1496:1-9.
Focal cerebral ischemia initiates self-repair mechanisms that include the production of neurotrophic factors and cytokines. Galectin-3 is an important angiogenic cytokine. We have previously demonstrated that expression of galectin 3 (Gal-3), a carbohydrate binding protein is significantly upregulated in activated microglia in the brains of rats subjected to focal ischemia. Further blocking of Gal-3 function with Gal-3 neutralizing antibody decreased the microvessel density in ischemic brain. We currently show that Gal-3 significantly increases the viability of microglia BV2 cells subjected to oxygen glucose deprivation (OGD) and re-oxygenation. Exogenous Gal-3 promoted the formation of pro-angiogenic structures in an in vitro human umbilical vein endothelial (HUVEC) and BV2 cell co-culture model. Gal-3 induced angiogenesis was associated with increased expression of vascular endothelial growth factor. The conditioned medium of BV2 cells exposed to OGD contained increased Gal-3 levels, and promoted the formation of pro-angiogenic structures in an in vitro HUVEC culture model. Gal-3 also augmented the in vitro migratory potential of BV2 microglia. Gal-3 mediated functions were associated with increased levels of integrin-linked kinase (ILK) signaling as demonstrated by the impaired angiogenesis and migration of BV2 cells following targeted silencing of ILK expression by SiRNA. Furthermore, we show that ILK levels correlate with the levels of phos-AKT and ERK1/2 that are downstream effectors of ILK pathway. Taken together, our studies indicate that Gal-3 contributes to angiogenesis and microglia migration that may have implications in post stroke repair.
PMCID: PMC4084961  PMID: 23246924
Survival; Angiogenesis; Migration; Galectin-3; ILK signaling; Ischemic injury
2.  Methanandamide attenuates cocaine-induced hyperthermia in rats by a cannabinoid CB1-dopamine D2 receptor mechanism 
Brain research  2009;10.1016/j.brainres.2008.12.078.
Evidence implicates anandamide in dopamine-related cocaine function. In the present study, we investigated the effect of methanandamide (5 mg/kg, i.p.), a stable anandamide analog, on the hyperthermia and hyperactivity induced by a fixed dose of cocaine (15 mg/kg, i.p.). Cocaine administered to rats produced hyperthermia and hyperactivity whereas methanandamide was ineffective. For combined administration, methanandamide attenuated the hyperthermia, but not hyperactivity, induced by cocaine. The effect of methanandamide was abolished by pretreatment with a cannabinoid CB1 receptor antagonist, SR141716A (5 mg/kg, i.p.), or dopamine D2 receptor antagonist, S(−)-raclopride (5 mg/kg, i.p.) but not by capsazepine (40 mg/kg, i.p.), a transient receptor potential vanilloid 1 cation channel antagonist. Methanandamide also attenuated the hyperthermia caused by a dopamine D1 receptor agonist, SKF 38393 (10 mg/kg, s.c.), indicating that it reduces hyperthermia produced by dopamine D1 receptor activation. URB597 (0.25 mg/kg, i.p.), an inhibitor of anandamide metabolism, did not alter cocaine-induced hyperthermia. Our results demonstrate that methanandamide activates cannabinoid CB1 receptors to attenuate cocaine-induced hyperthermia, and that dopamine D2 receptor activation plays a permissive role in the thermoregulatory effects of methanandamide.
PMCID: PMC4081499  PMID: 19401177
Anandamide; Cannabinoid; Cocaine; Psychostimulant; Dopamine; Hyperthermia; Methanandamide; D2; D1; SKF 38393; URB597; Raclopride; CB1
3.  Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Aβ42 oligomers via a metalloproteinase-dependent mechanism 
Brain research  2013;1520:145-156.
Soluble amyloid-β peptide (Aβ) oligomers have been hypothesized to be primary mediators of Alzheimer’s disease progression. In this regard, reduction of soluble Aβ-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Aβ levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26-9100 on the changes in learning and soluble Aβ42 oligomer brain content with and without co administration of the M13-metalloproteinase family enzyme-inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 μg i.c.v. in 2 μL) improved learning, which was blocked by phosphoramidon (1 and 10 mM, respectively). NNC 26-9100 decreased total soluble Aβ42, an effect which was blocked by phosphoramidon (10 mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the Aβ42 trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the Aβ42 hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10 mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble Aβ42 oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble Aβ42 oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism.
PMCID: PMC3686878  PMID: 23669069
Phosphoramidon, NNC 26-9100; Somatostatin receptor subtype-4; Amyloid beta oligomer
4.  Long-lasting distortion of GABA signaling in MS/DB neurons after binge-like ethanol exposure during initial synaptogenesis 
Brain research  2013;1520:36-50.
Using a well-established model of binge-like ethanol treatment of rat pups on postnatal days (PD) 4–9, we found that maturation of GABAA receptor (GABAAR) miniature postsynaptic currents (mPSCs) was substantially blunted for medial septum/diagonal band (MS/DB) neurons in brain slices on PD 11–16. Ethanol reduced mPSC amplitude, frequency, and decay kinetics, while attenuating or exaggerating allosteric actions of zolpidem and allopregnanolone, respectively. The impact of ethanol in vivo was long lasting as most changes in MS/DB GABAAR mPSCs were still observed as late as PD 60–85. Maturing MS/DB neurons in naïve brain slices PD 4–16 showed increasing mPSC frequency, decay kinetics, and zolpidem sensitivity that were nearly identical to our earlier findings in cultured septal neurons [17, 18]. These rapidly developing mPSC parameters continued to mature through the first month of life then stabilized throughout the remainder of the lifespan. Finally, equivalent ethanol-induced alterations in GABAAR mPSC signaling were present in MS/DB neurons from both male and female animals. Previously, we showed ethanol treatment of cultured embryonic day 20 septal neurons distorts the maturation of GABAAR mPSCs predicting that early stages of GABAergic transmission in MS/DB neurons are vulnerable to intoxication injury [17, 18]. Since the overall character, timing, and magnitude of GABAergic mPSC developmental- and ethanol-induced changes in the in vivo model so closely mirror chronologically equivalent adaptations in cultured septal neurons, this suggests that such parallel models of ethanol impairment of GABAergic synaptic development in vivo and in vitro should be useful for translational studies exploring the efficacy and mechanism of action of potential therapeutic interventions from the cellular to whole animal level.
PMCID: PMC3722596  PMID: 23685190
Fetal alcohol spectrum disorder; GABAA receptor; Miniature postsynaptic current; Medial septum/diagonal band; Development; Zolpidem; Allopregnanolone
5.  Cerebral cortical blood flow maps are reorganized in MAOB-deficient mice 
Brain research  1999;824(1):36-44.
Cerebral cortical blood flow (CBF) was measured autoradiographically in conscious mice without the monoamine oxidase B (MAOB) gene (KO, n = 11) and the corresponding wild-type animals (WILD, n = 11). Subgroups of animals of each genotype received a continuous intravenous infusion over 30 min of phenylethylamine (PEA), an endogenous substrate of MAOB, (8 nmol g−1 min−1 in normal saline at a volume rate of 0.11 μl g−1 min−1) or saline at the same volume rate. Maps of relative CBF distribution showed predominance of midline motor and sensory area CBF in KO mice over WILD mice that received saline. PEA enhanced CBF in lateral frontal and piriform cortex in both KO and WILD mice. These changes may reflect a differential activation due to chronic and acute PEA elevations on motor and olfactory function, as well as on the anxiogenic effects of this amine. In addition to its effects on regional CBF distribution, PEA decreased CBF globally in KO mice (range −31% to −41% decrease from control levels) with a lesser effect in WILD mice. It is concluded that MAOB may normally regulate CBF distribution and its response to blood PEA.
PMCID: PMC4075434  PMID: 10095040
Cerebral blood flow; Monoamine oxidase; Phenylethylamine; Autoradiography; Iodo-antipyrine; Mouse
7.  Neuronal Expression of Soluble Adenylyl Cyclase in the Mammalian Brain 
Brain research  2013;1518:1-8.
Cyclic 3’, 5’-adenosine monophosphate (cAMP) is a critical and ubiquitous second messenger involved in a multitude of signaling pathways. Soluble adenylyl cyclase (sAC) is a novel source of cAMP subject to unique localization and regulation. It was originally discovered in mammalian testis and found to be activated by bicarbonate and calcium. sAC has been implicated in diverse processes, including astrocyte-neuron metabolic coupling and axonal outgrowth of neurons. However, despite these functional studies, demonstration of sAC protein expression outside of testis has been controversial. Recently, we showed sAC immunoreactivity in astrocytes, but the question of neuronal expression of sAC remained. We now describe the generation of a second sAC knockout mouse model (C2KO) designed to more definitively address questions of sAC expression, and we demonstrate conclusively using immune-electron microscopy that sAC is expressed in neuronal profiles in the central nervous system.
PMCID: PMC3679342  PMID: 23611875
Cyclic AMP (cAMP); cerebellum; hippocampus; visual cortex; adenylyl cyclase
8.  COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest 
Brain research  2013;1519:71-77.
Cyclopentenone prostaglandins have been identified as potential neurotoxic agents in the setting of hypoxia-ischemia. Cyclooxygenase-2 (COX-2), the upstream enzyme responsible for prostaglandin production is upregulated following hypoxic-ischemic brain injury. However, the temporal production and concentration of cyclopentenone prostaglandins has not been described following global brain ischemia.
Global brain ischemia was induced in rats by asphyxial cardiac arrest (ACA) followed by resuscitation. Rats were sacrificed between 24 hours and 7 days following resuscitation and their brains removed. Western blot, immunohistochemistry, and mass spectroscopy were performed. A cohort of rats was pretreated with the COX-2 inhibitor SC58125.
COX-2 is induced in hippocampus at 24 hours following ACA. Multiple prostaglandins, including cyclopentenone prostaglandin species, are increased in hippocampus as 24 hours following ACA. Prostaglandin and cyclopentenone prostaglandin concentrations are returned to baseline at 3 and 7 days post-ischemia. The COX-2 inhibitor SC58125 completely abrogates the post-ischemic increase in prostaglandins and cyclopentenone prostaglandins.
Prostaglandins, including cyclopentenone prostaglandins, are increased in ischemic brain, peak at 24 hours and can be attenuated by the COX-2 inhibitor SC58125. These data establish the presence of potentially neurotoxic cyclopentenone prostaglandins in post-ischemic brains, thus identifying a target and therapeutic window for neuroprotective therapies.
PMCID: PMC3681205  PMID: 23624225
9.  Striatal oligodendrogliogenesis and neuroblast recruitment are increased in the R6/2 mouse model of Huntington's disease 
Brain research  2013;1518:91-103.
The subventricular zone (SVZ) is one of the two major neurogenic regions in the adult mammalian brain. Its close proximity to the striatum suggests that a cell-based therapeutic strategy for the treatment of Huntington’s disease (HD) is possible. To achieve this, it is important to understand how adult cell production, migration and differentiation may be altered in the HD brain. In this study, we quantified the number of adult-born striatal cells and characterized their fate in the R6/2 transgenic mouse model of HD. We found that the number of new striatal cells was approximately two-fold greater in R6/2 versus wild type mice, while SVZ cell proliferation was not affected. Using cell-type specific markers, we demonstrated that the majority of new striatal cells were mature oligodendrocytes or oligodendroglial precursors that were intrinsic to the striatum. We also detected a significant increase in the number of migrating neuroblasts that appeared to be recruited from the SVZ to the striatum. However, these neuroblasts did not mature into neurons and most were lost between 1 and 2 weeks of cell age. Crossing the R6/2 mice with mice over-expressing brain-derived neurotrophic factor in the striatum increased the numbers of neuroblasts that survived to 2 weeks, but did not promote their differentiation. Together, our data indicate that the potential treatment of HD based on manipulating endogenous progenitor cells should take into consideration the apparent enhancement in striatal oligodendrogliogenesis and the limited ability of recruited SVZ neuroblasts to survive long-term and differentiate in the diseased striatum.
PMCID: PMC3684253  PMID: 23623813
Huntington’s disease; adult neurogenesis; oligodendroglia; neuroblast; brain derived neurotrophic factor
10.  Distribution of CaMKIIα expression in the brain in vivo, studied by CaMKIIα-GFP mice 
Brain research  2013;1518:9-25.
To facilitate the study of the CaMKIIα function in vivo, a CaMKIIα-GFP transgenic mouse line was generated. Here, our goal is to provide the first neuroanatomical characterization of GFP expression in the CNS of this line of mouse. Overall, CaMKIIα -GFP expression is strong and highly heterogeneous, with the dentate gyrus of the hippocampus as the most abundantly expressed region. In the hippocampus, around 70% of granule and pyramidal neurons expressed strong GFP. In the neocortex, presumed pyramidal neurons were GFP positive: around 32% of layer II/III and 35% of layer VI neurons expressed GFP, and a lower expression rate was found in other layers. In the thalamus and hypothalamus, strong GFP signals were detected in the neuropil. GFP-positive cells were also found in many other regions such as the spinal trigeminal nucleus, cerebellum and basal ganglia. We further compared the GFP expression with specific antibody staining for CaMKIIα and GABA. We found that GFP+ neurons were mostly positive for CaMKIIα-IR throughout the brain, with some exceptions throughout the brain, especially in the deeper layers of neocortex. GFP and GABA-IR marked distinct neuronal populations in most brain regions with the exception of granule cells in the olfactory bulb, purkinje cells in the cerebellar, and some layer I cells in neocortex. In conclusion, GFP expression in the CaMKIIα-GFP mice is similar to the endogenous expression of CaMKIIα protein, thus these mice can be used in in vivo and in vitro physiological studies in which visualization of CaMKIIα- neuronal populations is required.
PMCID: PMC3747672  PMID: 23632380
Calmodulin; Ca2+/CaM-activated protein kinase II alpha; green fluorescent protein; dentate gyrus; CA1; cerebellum; neocortex; hypothalamus; thalamus; CNS
11.  The influences of reproductive status and acute stress on the levels of phosphorylated delta opioid receptor immunoreactivity in rat hippocampus☆ 
Brain research  2013;1518:71-81.
In the hippocampus, ovarian hormones and sex can alter the trafficking of delta opioid receptors (DORs) and the proportion of DORs that colocalize with the stress hormone, corticotropin releasing factor. Here, we assessed the effects of acute immobilization stress (AIS) and sex on the phosphorylation of DORs in the rat hippocampus. We first localized an antibody to phosphorylated DOR (pDOR) at the SER363 carboxy-terminal residue, and demonstrated its response to an opioid agonist. By light microscopy, pDOR-immunoreactivity (ir) was located predominantly in CA2/CA3a pyramidal cell apical dendrites and in interneurons in CA1-3 stratum oriens and the dentate hilus. By electron microscopy, pDOR-ir primarily was located in somata and dendrites, associated with endomembranes, or in dendritic spines. pDOR-ir was less frequently found in mossy fibers terminals. Quantitative light microscopy revealed a significant increase in pDOR-ir in the CA2/CA3a region of male rats 1 h following an injection of the opioid agonist morphine (20 mg/kg, I.P). To look at the effects of stress on pDOR, we compared pDOR-ir in males and cycling females after AIS. The level of pDOR-ir in stratum radiatum of CA2/CA3a was increased in control estrus (elevated estrogen and progesterone) females compared to proestrus and diestrus females and males. However, immediately following 30 min of AIS, no significant differences in pDOR levels were seen across estrous cycle phase or sex. These findings suggest that hippocampal levels of phosphorylated DORs vary with estrous cycle phase and that acute stress may dampen the differential effects of hormones on DOR activation in females.
PMCID: PMC3764923  PMID: 23583481
Opioids; Sex differences; Estrogens; CA2 region of the hippocampus; Pyramidal cells; Mossy fiber pathway
12.  Patterns of phosphorylated tyrosine hydroxylase vary with song production in female starlings 
Brain research  2012;S0006-8993(12)01931-2 10.1016/j.brainres.2012.12.020.
Vocal signal production in male songbirds is well studied, but the neural correlates of female song production are poorly understood. In European starlings, females sing to defend nesting resources, and song can be considered agonistically motivated. Across vertebrates catecholamines strongly influence motivated, agonistic social behaviors. The present study was designed to provide insight into a possible role for catecholamine activity in territorial song in female starlings. We presented females that were defending nest-cavities with an unfamiliar female and assessed song production. We then measured immunolabeling for phosphorylated tyrosine hydroxylase (pTH-ir), a rate-limiting enzyme for catecholamine synthesis, in brain regions in which catecholamines stimulate agonistic behavior. Females that sang had higher pTH-ir in the caudomedial ventral tegmental area and the lateral septum than females that did not sing. Furthermore, the number of songs produced correlated positively with pTH-ir in the medial preoptic nucleus. Phosphorylation of TH is thought to occur after catecholamine release, so these results link increased catecholamine activity in several brain regions governing agonistic behavior to territorial song production in females.
PMCID: PMC3758383  PMID: 23270608
norepinephrine; dopamine; motivation; communication; social behavior; female song
13.  Activated protein C analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact 
Brain research  2010;1347:125-131.
The anticoagulant activated protein C (APC) protects neurons and vascular cells from injury through its direct cytoprotective effects that are independent of its anticoagulant action. Wild-type recombinant murine APC (wt-APC) exerts significant neuroprotection in mice if administered early after traumatic brain injury (TBI). Here, we compared efficacy and safety of a late therapy for TBI with wt-APC and 3K3A-APC, an APC analog with ~80% reduced anticoagulant activity but normal cytoprotective activity, using a controlled cortical impact model of TBI. Mice received 0.8 mg/kg intraperitoneally of recombinant murine 3K3A-APC, wt-APC or saline at 6, 12, 24 and 48 h after injury. 3K3A-APC (n=15) relative to wt-APC (n=15) improved motor and sensorimotor recovery within the first three days post-trauma as demonstrated by rotarod (p<0.05) and beam balance test (p<0.05), respectively. Both, wt-APC and 3K3A-APC reduced the lesion volume seven days after injury by 36% (n=8; p<0.01) and 56% (n=8; p<0.01), respectively, compared to saline (n=8). Three days post-TBI, the hemoglobin levels in the injured brain were increased by ~3-fold after wt-APC treatment compared to saline indicating an increased risk for intracerebral bleeding. In contrast, comparable levels of brain hemoglobin in 3K3A-APC-treated and saline-treated mice suggested that 3K3A-APC treatment did not increase risk for bleeding after TBI. Thus, compared to wt-APC, 3K3A-APC is more efficacious and safer therapy for TBI with no risk for intracerebral hemorrhage.
PMCID: PMC4068704  PMID: 20513369
Activated protein C analog; Traumatic brain injury; Neuroprotection; Hemorrhage
14.  Estradiol Modulates Neurotransmitter Concentrations in the Developing Zebra Finch Song System 
Brain research  2013;1517:87-92.
The neural song system in zebra finches is highly sexually dimorphic; only males sing and the brain regions controlling song are far larger in males than females. Estradiol (E2) administered during development can partially masculinize both structure and function. However, additional mechanisms, including those through which E2 may act, remain unclear. Male and female zebra finches were treated with E2 or control vehicle from post-hatching days 3 through 25, at which time norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were measured in individual nuclei of the song system. Main effects of sex were not detected. However, E2 increased NE in the robust nucleus of the arcopallium (RA). In HVC (proper name), the hormone decreased 5-HT across the two sexes and increased DA in females only. These effects suggest that, while baseline levels of these neurotransmitters may not contribute to sexually dimorphic development of the song system, they could play specific roles in functions common to both sexes and/or in modification of the song system by exogenous E2.
PMCID: PMC3674499  PMID: 23628476
songbird; sexual differentiation; norepinephrine; dopamine; serotonin; steroid hormone
15.  Accumbal opioid receptors modulate cue competition in one-trial overshadowing 
Brain research  2013;1517:57-67.
The contribution of opioid receptors in the nucleus accumbens to contextual and auditory fear conditioning was examned. Impairment in contextual fear conditioning was found when training occurred under accumbal infusions of the opioid receptor agonist morphine in a dose-dependent and receptor specific fashion, only when shock onset coincided with auditory stimulus offset. Contextual fear conditioning was spared, however when the delivery of shock was not signalled by an auditory stimulus, the auditory stimulus was of low intensity (70dB), or an interval (10s or 30s) was interpolated between auditory stimulus offset and shock onset. These results provide evidence that opioid receptors in the nucleus accumbens regulate competition between contextual and discrete auditory stimuli for association formation.
PMCID: PMC3705635  PMID: 23603410
fear; rat; ventral striatum; attention; morphine; learning; memory
16.  Ultrastructure of spines and associated terminals on brainstem neurons controlling auditory input 
Brain research  2013;1516:1-10.
Spines are unique cellular appendages that isolate synaptic input to neurons and play a role in synaptic plasticity. Using the electron microscope, we studied spines and their associated synaptic terminals on three groups of brainstem neurons: tensor tympani motoneurons, stapedius motoneurons, and medial olivocochlear neurons, all of which exert reflexive control of processes in the auditory periphery. These spines are generally simple in shape; they are infrequent and found on the somata as well as the dendrites. Spines do not differ in volume among the three groups of neurons. In all cases, the spines are associated with a synaptic terminal that engulfs the spine rather than abuts its head. The positions of the synapses are variable, and some are found at a distance from the spine, suggesting that the isolation of synaptic input is of diminished importance for these spines. Each group of neurons receives three common types of synaptic terminals. The type of terminal associated with spines of the motoneurons contains pleomorphic vesicles, whereas the type associated with spines of olivocochlear neurons contains large round vesicles. Thus, spine-associated terminals in the motoneurons appear to be associated with inhibitory processes but in olivocochlear neurons they are associated with excitatory processes.
PMCID: PMC3741616  PMID: 23602963
Olivocochlear; Stapedius; Tensor tympani; Middle ear muscle; Vesicle morphometry; Electron microscopy
17.  Peripubertal proliferation of progenitor cells in the preoptic area of Japanese quail (Coturnix japonica) 
Brain research  2013;1516:20-32.
Brain structures related to reproduction are thought to depend on the action of gonadal steroids acting either during early life (organizing irreversible effects) or adulthood (activating transient effects). More recently puberty has become a focus of attention and it was demonstrated that action of sex steroid hormones at this time plays a critical role in the final organization of brain and behavior. We studied by BrdU immunohistochemistry the ontogeny from hatching to sexual maturity of a previously identified cell population in the preoptic area labeled by a BrdU injection at the end of embryonic period (E12) of sexual differentiation in male and female Japanese quail. After an initial increase between E12 and hatching, the density of BrdU-immunoreactive cells decreased until the beginning of puberty but then increased again during sexual maturation in the caudal preoptic area specifically. Divisions of these cells took place in the brain parenchyma as indicated by the large numbers of pairs of labeled cells. No sex difference affecting these processes could be detected at any stage of development. Large numbers of new cells thus arise around puberty in the caudal preoptic area and presumably contribute to the reorganization of this structure that precedes the emergence of adult reproductive behaviors.
PMCID: PMC3755345  PMID: 23623814
Embryogenesis; Puberty; Progenitor cell; Preoptic area; Sexual behavior; Brain plasticity
18.  Senescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline 
Brain research  2013;1516:93-109.
It is well known that alongside senescence there is a gradual decline in cognitive ability, most noticeably certain kinds of memory such as working, episodic, spatial, and long term memory. However, until recently, not much has been known regarding the specific mechanisms responsible for the decline in cognitive ability with age. Over the past decades, researchers have become more interested in cAMP signaling, and its downstream transcription factor cAMP response element binding protein (CREB) in the context of senescence. However, there is still a lack of understanding on what ultimately causes the cognitive deficits observed with senescence. This review will focus on the changes in intracellular signaling in the brain, more specifically, alterations in cAMP/CREB signaling in aging. In addition, the downstream effects of altered cAMP signaling on cognitive ability with age will be further discussed. Overall, understanding the senescent-related changes that occur in cAMP/CREB signaling could be important for the development of novel drug targets for both healthy aging, and pathological aging such as Alzheimer's disease.
PMCID: PMC3760033  PMID: 23623816
Aging; Memory; Camp; CREB; Phosphodiesterase; Protein kinase A
19.  NAAG Peptidase Inhibitor Improves Motor Function and Reduces Cognitive Dysfunction in a Model of TBI with Secondary Hypoxia 
Brain research  2013;1515:98-107.
Immediately following traumatic brain injury (TBI) and TBI with hypoxia, there is a rapid and pathophysiological increase in extracellular glutamate, subsequent neuronal damage and ultimately diminished motor and cognitive function. N-acetyl-aspartyl glutamate (NAAG), a prevalent neuropeptide in the CNS, is co-released with glutamate, binds the presynaptic mGluR3 (group II metabotropic glutamate receptor) and suppresses glutamate release. However, the catalytic enzyme glutamate carboxypeptidase II (GCPII) rapidly hydrolyzes NAAG into NAA and glutamate. Inhibition of the GCPII enzyme with NAAG peptidase inhibitors reduces the concentration of glutamate both by increasing the duration of NAAG activity on mGluR3 and by reducing degradation into NAA and glutamate resulting in reduced cell death in models of TBI and TBI with hypoxia. In the following study, rats were administered the NAAG peptidase inhibitor PGI-02776 (10 mg/kg) 30 min following TBI combined with a hypoxic second insult. Over the two weeks following injury, PGI-02776 treated rats had significantly improved motor function as measured by increased duration on the rota-rod and a trend toward improved performance on the beam walk. Furthermore, two weeks post-injury, PGI-02776-treated animals had a significant decrease in latency to find the target platform in the Morris water maze as compared to vehicle-treated animals. These findings demonstrate that the application of NAAG peptidase inhibitors can reduce the deleterious motor and cognitive effects of TBI combined with a second hypoxic insult in the weeks following injury.
PMCID: PMC3672358  PMID: 23562458
Traumatic brain injury (TBI); Hypoxia; Excitotoxicity; N-acetylaspartylglutamate (NAAG); Behavior; Pre-clinical
20.  The rationale, design, and baseline characteristics of the Women’s Health Initiative Memory Study of Younger Women (WHIMS-Y) 
Brain research  2013;1514:3-11.
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
PMCID: PMC3684042  PMID: 23578696
Postmenopausal hormone therapy; Cognitive function; Aging
21.  Factors influencing the cognitive and neural effects of hormone treatment during aging in a rodent model 
Brain research  2013;1514:40-49.
Whether hormone treatment alters brain structure or has beneficial effects on cognition during aging has recently become a topic of debate. Although previous research has indicated that hormone treatment benefits memory in menopausal women, several newer studies have shown no effect or detrimental effects. These inconsistencies emphasize the need to evaluate the role of hormones in protecting against age-related cognitive decline in an animal model. Importantly, many studies investigating the effects of estrogen and progesterone on cognition and related brain regions have used young adult animals, which respond differently than aged animals. However, when only the studies that have examined the effects of hormone treatment in an aging model are reviewed, there are still varied behavioral and neural outcomes. This article reviews some of the important factors that can influence the behavioral and neural outcomes of hormone treatment including the type of estrogen administered, whether or not estrogen is combined with progesterone and if so, the type of progesterone used, as well as the route, mode, and length of treatment. How these factors influence cognitive outcomes highlights the importance of study design and avoiding generalizations from a small number of studies.
PMCID: PMC3672353  PMID: 23419893
estradiol; progesterone; cognition; prefrontal cortex; memory; aging; menopause; medroxyprogesterone; estrogen; hippocampus
22.  Progesterone-induced Neuroprotection: Factors that may predict therapeutic efficacy 
Brain research  2013;1514:98-106.
Both progesterone and estradiol have well-described neuroprotective effects against numerous insults in a variety of cell culture models, animal models and in humans. However, the efficacy of these hormones may depend on a variety of factors, including the type of hormone used (ex. progesterone versus medroxyprogesterone acetate), the duration of the postmenopausal period prior to initiating the hormone intervention, and potentially, the age of the subject. The latter two factors relate to the proposed existence of a “window of therapeutic opportunity” for steroid hormones in the brain. While such a window of opportunity has been described for estrogen, there is a paucity of information to address whether such a window of opportunity exists for progesterone and its related progestins. Here, we review known cellular mechanisms likely to underlie the protective effects of progesterone and furthermore, describe key differences in the neurobiology of progesterone and the synthetic progestin, medroxyprogesterone acetate (MPA). Based on the latter, we offer a model that defines some of the key cellular and molecular players that predict the neuroprotective efficacy of progesterone. Accordingly, we suggest how changes in the expression or function of these cellular and molecular targets of progesterone with age or prolonged duration of hormone withdrawal (such as following surgical or natural menopause) may impact the efficacy of progesterone.
PMCID: PMC3672388  PMID: 23340161
23.  Potentiation of Brain Mitochondrial Function by S-equol and R/S-equol Estrogen Receptor β Selective PhytoSERM Treatments 
Brain research  2013;1514:128-141.
Previously we developed an estrogen receptor β-selective phytoestrogenic (phytoSERM) combination, which contains a mixture of genistein, daidzein, and racemic R/S-equol. The phytoSERM combination was found neuroprotective and non-feminizing both in vitro and in vivo. Further, it prevented or alleviated physical and neurological changes associated with human menopause and Alzheimer’s disease. In the current study, we conducted translational analyses to compare the effects of racemic R/S-equol-containing with S-equol-containing phytoSERM therapeutic combinations on mitochondrial markers in rat hippocampal neuronal cultures and in a female mouse ovariectomy (OVX) model. Data revealed that both the S-equol and R/S-equol phytoSERM treatments regulated mitochondrial function, with S-equol phytoSERM combination eliciting greater response in mitochondrial potentiation. Both phytoSERM combination treatments increased expression of key proteins and enzymes involved in energy production, restored the OVX-induced decrease in activity of key bioenergetic enzymes, and reduced OVX-induced increase in lipid peroxidation. Comparative analyses on gene expression profile revealed similar regulation between S-equol phytoSERM and R/S-equol phytoSERM treatments with minimal differences. Both combinations regulated genes involved in essential bioenergetic pathways, including glucose metabolism and energy sensing, lipid metabolism, cholesterol trafficking, redox homeostasis and β-amyloid production and clearance. Further, no uterotrophic response was induced by either of the phytoSERM combinations. These findings indicate translational validity for development of an ER β selective S-equol phytoSERM combination as a nutraceutical to prevent menopause-associated symptoms and to promote brain metabolic activity.
PMCID: PMC3672394  PMID: 23428542
equol; phytoSERM; mitochondria; oxidative stress; bioenergetics
24.  Window Of Opportunity: Estrogen As A Treatment For Ischemic Stroke✰ 
Brain research  2013;1514:83-90.
The neuroprotection research in the last 2 decades has witnessed a growing interest in the functions of estrogens as neuroprotectants against neurodegenerative diseases including stroke. The neuroprotective action of estrogens has been well demonstrated in both in vitro and in vivo models of ischemic stroke. However, the major conducted clinical trials so far have raised concern for the protective effect of estrogen replacement therapy in postmenopausal women. The discrepancy could be partly due to the mistranslation between the experimental stroke research and clinical trials. While predominant experimental studies tested the protective action of estrogens on ischemic stroke using acute treatment paradigm, the clinical trials have mainly focused on the effect of estrogen replacement therapy on the primary and secondary stroke prevention which has not been adequately addressed in the experimental stroke study. Although the major conducted clinical trials have indicated that estrogen replacement therapy has an adverse effect and raise concern for long term estrogen replacement therapy for stroke prevention, these are not appropriate for assessing the potential effects of acute estrogen treatment on stroke protection. The well established action of estrogen in the neurovascular unit and its potential interaction with recombinant tissue plasminogen activator (rtPA) makes it a candidate for the combined therapy with rtPA for the acute treatment of ischemic stroke. On the other hand, the “critical period” and newly emerged “biomarkers window” hypotheses have indicated that many clinical relevant factors have been underestimated in the experimental ischemic stroke research. The development and application of ischemic stroke models that replicate the clinical condition is essential for further evaluation of acute estrogen treatment on ischemic stroke which might provide critical information for future clinical trials.
PMCID: PMC3664650  PMID: 23340160
estrogen; stroke; ischemia; neuroprotection; neurovascular unit; recombinant tissue plasminogen activator
25.  Does phytoestrogen supplementation affect cognition differentially in males and females? 
Brain research  2013;1514:123-127.
Phytoestrogens are plant-derived compounds found mainly in soy with known estrogenic properties and a potential for benefits to human health. Increased intake in phytoestrogens stemmed from the search for safe alternatives to hormone replacement therapies. Based on epidemiologic evidence comparing Western and Asian population and clinical studies, phytoestrogens show promise to improve health and brain function. This review will focus on the effects of phytoestrogens on cognition by examining clinical and animals studies, with special attention placed on (1) a window of therapeutic opportunity which may explains the discrepancy amongst studies, and (2) whether a sex/gender difference exists in response to phytoestrogen intake and what the possible underlying mechanisms may be.
PMCID: PMC3677816  PMID: 23415935

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