Prenatal Cannabinoid Exposure Elicits Memory Deficits Associated with Reduced PSA-NCAM Expression, Altered Glutamatergic Signaling, and Adaptations in Hippocampal Synaptic Plasticity.

Cannabis is now one of the most commonly used illicit substances among pregnant women. This is particularly concerning since developmental exposure to cannabinoids can elicit enduring neurofunctional and cognitive alterations. This study investigates the mechanisms of learning and memory deficits resulting from prenatal cannabinoid exposure (PCE) in adolescent offspring. The synthetic cannabinoid agonist WIN55,212-2 was administered to pregnant rats, and a series of behavioral, electrophysiological, and immunochemical studies were performed to identify potential mechanisms of memory deficits in the adolescent offspring. Hippocampal-dependent memory deficits in adolescent PCE animals were associated with decreased long-term potentiation (LTP) and enhanced long-term depression (LTD) at hippocampal Schaffer collateral-CA1 synapses, as well as an imbalance between GluN2A- and GluN2B-mediated signaling. Moreover, PCE reduced gene and protein expression of neural cell adhesion molecule (NCAM) and polysialylated-NCAM (PSA-NCAM), which are critical for GluN2A and GluN2B signaling balance. Administration of exogenous PSA abrogated the LTP deficits observed in PCE animals, suggesting PSA mediated alterations in GluN2A- and GluN2B- signaling pathways may be responsible for the impaired hippocampal synaptic plasticity resulting from PCE. These findings enhance our current understanding of how PCE affects memory and how this process can be manipulated for future therapeutic purposes.

Phenyl-2-aminoethyl selenide ameliorates hippocampal long-term potentiation and cognitive deficits following doxorubicin treatment.

Chemotherapy-induced memory loss ("chemobrain") can occur following treatment with the widely used chemotherapeutic agent doxorubicin (DOX). However, the mechanisms through which DOX induces cognitive dysfunction are not clear, and there are no commercially available therapies for its treatment or prevention. Therefore, the aim of this study was to determine the therapeutic potential of phenyl-2-aminoethyl selenide (PAESe), an antioxidant drug previously demonstrated to reduce cardiotoxicity associated with DOX treatment, against DOX-induced chemobrain. Four groups of male athymic NCr nude (nu/nu) mice received five weekly tail-vein injections of saline (Control group), 5 mg/kg of DOX (DOX group), 10 mg/kg PAESe (PAESe group), or 5 mg/kg DOX and 10 mg/kg PAESe (DOX+PAESe group). Spatial memory was evaluated using Y-maze and novel object location tasks, while synaptic plasticity was assessed through the measurement of field excitatory postsynaptic potentials from the Schaffer collateral circuit. Western blot analyses were performed to assess hippocampal protein and phosphorylation levels. In this model, DOX impaired synaptic plasticity and memory, and increased phosphorylation of protein kinase B (Akt) and extracellular-regulated kinase (ERK). Co-administration of PAESe reduced Akt and ERK phosphorylation and ameliorated the synaptic and memory deficits associated with DOX treatment.

Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer's Disease.

Background: The continuously increasing association of Alzheimer's disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer's disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD.

Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.

Dysregulated cortical expression of the neural cell adhesion molecule (NCAM) and deficits of its associated polysialic acid (polySia) have been found in Alzheimer's disease and schizophrenia. However, the functional role of polySia in cortical synaptic plasticity remains poorly understood. Here, we show that acute enzymatic removal of polySia in medial prefrontal cortex (mPFC) slices leads to increased transmission mediated by the GluN1/GluN2B subtype of N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-mediated extrasynaptic tonic currents, and impaired long-term potentiation (LTP). The latter could be fully rescued by pharmacological suppression of GluN1/GluN2B receptors, or by application of short soluble polySia fragments that inhibited opening of GluN1/GluN2B channels. These treatments and augmentation of synaptic NMDARs with the glycine transporter type 1 (GlyT1) inhibitor sarcosine also restored LTP in mice deficient in polysialyltransferase ST8SIA4. Furthermore, the impaired performance of polySia-deficient mice and two models of Alzheimer's disease in the mPFC-dependent cognitive tasks could be rescued by intranasal administration of polySia fragments. Our data demonstrate the essential role of polySia-NCAM in the balancing of signaling through synaptic/extrasynaptic NMDARs in mPFC and highlight the therapeutic potential of short polySia fragments to restrain GluN1/GluN2B-mediated signaling.

Recent Insights on Glutamatergic Dysfunction in Alzheimer's Disease and Therapeutic Implications.

Alzheimer's disease (AD) poses a critical public health challenge, and there is an urgent need for novel treatment options. Glutamate, the principal excitatory neurotransmitter in the human brain, plays a critical role in mediating cognitive and behavioral functions; and clinical symptoms in AD patients are highly correlated with the loss of glutamatergic synapses. In this review, we highlight how dysregulated glutamatergic mechanisms can underpin cognitive and behavioral impairments and contribute to the progression of AD via complex interactions with neuronal and neural network hyperactivity, Aß, tau, glial dysfunction, and other disease-associated factors. We focus on the tripartite synapse, where glutamatergic neurotransmission occurs, and evidence elucidating how the tripartite synapse can be pathologically altered in AD. We also discuss promising therapeutic approaches that have the potential to rescue these deficits. These emerging data support the development of novel glutamatergic drug candidates as compelling approaches for treating AD.

Differential Effects of Human P301L Tau Expression in Young versus Aged Mice.

The greatest risk factor for developing Alzheimer's disease (AD) is increasing age. Understanding the changes that occur in aging that make an aged brain more susceptible to developing AD could result in novel therapeutic targets. In order to better understand these changes, the current study utilized mice harboring a regulatable mutant P301L human tau transgene (rTg(TauP301L)4510), in which P301L tau expression can be turned off or on by the addition or removal of doxycycline in the drinking water. This regulatable expression allowed for assessment of aging independent of prolonged mutant tau expression. Our results suggest that P301L expression in aged mice enhances memory deficits in the Morris water maze task. These behavioral changes may be due to enhanced late-stage tau pathology, as evidenced by immunoblotting and exacerbated hippocampal dysregulation of glutamate release and uptake measured by the microelectrode array technique. We additionally observed changes in proteins important for the regulation of glutamate and tau phosphorylation that may mediate these age-related changes. Thus, age and P301L tau interact to exacerbate tau-induced detrimental alterations in aged animals.

Doxorubicin induces dysregulation of AMPA receptor and impairs hippocampal synaptic plasticity leading to learning and memory deficits.

Doxorubicin (Dox) is a chemotherapeutic agent used widely to treat a variety of malignant cancers. However, Dox chemotherapy is associated with several adverse effects, including "chemobrain," the observation that cancer patients exhibit through learning and memory difficulties extending even beyond treatment. This study investigated the effect of Dox treatment on learning and memory as well as hippocampal synaptic plasticity. Dox-treated mice (5 mg/kg weekly x 5) demonstrated impaired performance in the Y-maze spatial memory task and a significant reduction in hippocampal long-term potentiation. The deficit in synaptic plasticity was mirrored by deficits in the functionality of synaptic `α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) channels, including reduced probability of opening, decreased dwell open time, and increased closed times. Furthermore, a reduction in the AMPAR subunit GluA1 level, its downstream signaling molecule Ca2+/calmodulin-dependent protein kinase (CaMKII), and brain-derived neurotrophic factor (BDNF) were observed. This was also accompanied by an increase in extracellular signal regulated kinase (ERK) and protein kinase B (AKT) activation. Together these data suggest that Dox-induced cognitive impairments are at least partially due to alterations in the expression and functionality of the glutamatergic AMPAR system.

ß-hydroxybutyric acid attenuates oxidative stress and improves markers of mitochondrial function in the HT-22 hippocampal cell line.

Ketone bodies have been the topic of research for their possible therapeutic neurotropic effects in various neurological diseases such as Parkinson's disease, dementia, and seizures. However, continuing research on ketone bodies as a prophylactic agent for decreasing the risk for various neurodegenerative diseases is currently required. In this paper, hippocampal HT-22 cells were treated with ß-hydroxybutyric acid at different doses to elucidate the neurotropic effects. In addition, markers of oxidative stress, mitochondrial function, and apoptosis were investigated. As a result, the ketone body (ß-hydroxybutyric acid) showed a significant increase in hippocampal neuronal viability at a moderate dose. Results show that ß-hydroxybutyric acid exhibited antioxidant effect by decreasing prooxidant oxidative stress markers such as reactive oxygen species, nitrite content, and increasing glutathione content leading to decreased lipid peroxidation. Results show that ß-hydroxybutyric acid improved mitochondrial functions by increasing Complex-I and Complex-IV activities and showing that ß-hydroxybutyric acid significantly reduces caspase-1 and caspase-3 activities. Finally, using computational pharmacokinetics and molecular modeling software, we validated the pharmacokinetic effects and pharmacodynamic (N-Methyl-D-aspartic acid and acetylcholinesterase) interactions of ß-hydroxybutyric acid. The computational studies demonstrate that ß-hydroxybutyric acid can interact with N-Methyl-D-aspartic acid receptor and cholinesterase enzyme (the prime pharmacodynamic targets for cognitive impairment) and further validates its oral absorption, distribution into the central nervous system. Therefore, this work highlights the neuroprotective potential of ketone bodies in cognitive-related neurodegenerative diseases.

Effects of prenatal synthetic cannabinoid exposure on the cerebellum of adolescent rat offspring.

Cannabis is the most commonly used illicit drug worldwide. Recently, cannabis use among young pregnant women has greatly increased. However, prenatal cannabinoid exposure leads to long-lasting cognitive, motor, and behavioral deficits in the offspring and alterations in neural circuitry through various mechanisms. Although these effects have been studied in the hippocampus, the effects of prenatal cannabinoid exposure on the cerebellum are not well elucidated. The cerebellum plays an important role in balance and motor control, as well as cognitive functions such as attention, language, and procedural memories. The aim of this study was to investigate the effects of prenatal cannabinoid exposure on the cerebellum of adolescent offspring. Pregnant rats were treated with synthetic cannabinoid agonist WIN55,212-2, and the offspring were evaluated for various cerebellar markers of oxidative stress, mitochondrial function, and apoptosis. Additionally, signaling proteins associated with glutamate dependent synaptic plasticity were examined. Administration of WIN55,212-2 during pregnancy altered markers of oxidative stress by significantly reducing oxidative stress and nitrite content. Mitochondrial Complex I and Complex IV activities were also enhanced following prenatal cannabinoid exposure. With regard to apoptosis, pP38 levels were significantly increased, and proapoptotic factor caspase-3 activity, pERK, and pJNK levels were significantly decreased. CB1R and GluA1 levels remained unchanged; however, GluN2A was significantly reduced. There was a significant decrease in MAO activity although tyrosine hydroxylase activity was unaltered. Our study indicates that the effects of prenatal cannabinoid exposure on the cerebellum are unique compared to other brain regions by enhancing mitochondrial function and promoting neuronal survival. Further studies are required to evaluate the mechanisms by which prenatal cannabinoid exposure alters cerebellar processes and the impact of these alterations on behavior.

CRISPR/Cas9-mediated CysLT1R deletion reverses synaptic failure, amyloidosis and cognitive impairment in APP/PS1 mice.

As a major pathological hallmark of Alzheimer's disease (AD), amyloid-ß (Aß) is regarded as a causative factor for cognitive impairment. Extensive studies have found Aß induces a series of pathophysiological responses, finally leading to memory loss in AD. Our previous results demonstrated that cysteinyl leukotrienes receptor 1 (CysLT1R) antagonists improved exogenous Aß-induced memory impairment. But the role of CysLT1R in AD and its underlying mechanisms still remain elusive. In this study, we investigated CysLT1R levels in AD patients and APP/PS1 mice. We also generated APP/PS1-CysLT1R-/- mice by clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated CysLT1R deletion in APP/PS1 mice and studied the effect of CysLT1R knockout on amyloidogenesis, synapse structure and plasticity, cognition, neuroinflammation, and kynurenine pathway. These attributes were also studied after lentivirus-mediated knockdown of CysLT1R gene in APP/PS1 mice. We found that CysLT1R knockout or knockdown could conserve synaptic structure and plasticity, and improve cognition in APP/PS1 mice. These effects were associated with concurrent decreases in amyloid processing, reduced neuroinflammation and suppression of the kynurenine pathway. Our study demonstrates that CysLT1R deficiency can mediate several beneficial effects against AD pathogenesis, and genetic/pharmacological ablation of this protein could be a potential therapeutic option for AD.

The impact of cognitive impairment on survival and medication adherence among older women with breast cancer.

INTRODUCTION: The purpose of this study was to examine the impact of preexisting cognitive impairments on survival and medication adherence, and whether chronic medication adherence mediates or moderates the association between cognitive impairments and mortality in patients with breast cancer. METHODS: This retrospective cohort study of older female patients diagnosed with breast cancer was conducted using the Surveillance, Epidemiology, and End Results Medicare Linked Database. We examined the risk of mortality from cancer and non-cancer causes in patients with and without a history of cognitive impairment. In addition, we examined if chronic medication adherence rates differ between these groups of patients and if medication adherence mediates or moderates the association between cognitive impairments and non-cancer mortality. RESULTS: Mortality from cancer-specific (HR 1.13, 95% CI 1.04-1.23) and non-cancer causes (HR 1.16, 95% CI 1.11-1.21) as well as all-cause mortality (HR 1.30, 95% CI 1.23-1.38) was significantly higher in patients with cognitive impairments compared to those without cognitive impairment. Both groups showed low adherence levels to chronic medication before and after the breast cancer diagnosis. Further analysis did not show that medication adherence mediates or moderates the relationship between cognitive impairment and non-cancer mortality (p value > 0.05). CONCLUSION: The results of this study indicate that older female patients with cognitive impairments and a breast cancer diagnosis have a heightened risk of cancer-specific and non-cancer mortality. Our findings do not indicate that chronic medication adherence plays a role in the association between a history of cognitive impairment and mortality, it is still necessary to further investigate this issue.

Gut Metabolite TMAO Induces Synaptic Plasticity Deficits by Promoting Endoplasmic Reticulum Stress.

Dysbiosis of gut microbiota is strongly associated with metabolic diseases including diabetes mellitus, obesity, and cardiovascular disease. Recent studies indicate that Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite is implicated in the development of age-related cognitive decline. However, the mechanisms of the impact of TMAO on neuronal function has not been elucidated. In the current study, we investigated the relationship between TMAO and deficits in synaptic plasticity in an Alzheimer's model (3×Tg-AD) and insulin resistance (Leptin deficient db/db) mouse by measuring plasma and brain levels of TMAO. We observed increased TMAO levels in the plasma and brain of both db/db and 3×Tg-AD mice in comparison to wild-type mice. Besides, TMAO levels further increased as mice progressed in age. Deficits in synaptic plasticity, in the form of reduced long-term potentiation (LTP), were noted in both groups of mice in comparison to wild-type mice. To further explore the impact of TMAO on neuronal function, we utilized an ex-vivo model by incubating wild-type hippocampal brain slices with TMAO and found impaired synaptic transmission. We observed that TMAO induced the PERK-EIF2α-ER stress signaling axis in TMAO treated ex-vivo slices as well as in both db/db and 3×Tg-AD mice. Lastly, we also observed altered presynaptic and reduced postsynaptic receptor expression. Our findings suggest that TMAO may induce deficits in synaptic plasticity through the ER stress-mediated PERK signaling pathway. Our results offer novel insight into the mechanism by which TMAO may induce cognitive deficits by promoting ER stress and identifies potential targets for therapeutic intervention.

The association between antidepressants use and development of cognitive impairment among older women diagnosed with breast cancer.

PURPOSE: This study aimed to evaluate the association between the development of cognitive impairment and the use of antidepressants among older women with breast cancer. METHODS: This retrospective cohort study used the United States National Cancer Institute's Surveillance, Epidemiology, and End Results-Medicare database to identify women who were 67 years old and older and had breast cancer between 2008 and 2013. Propensity scoring was used to account for confounding pre-treatment factors, and Cox proportional hazards modeling was used to examine the risk of developing cognitive impairment among patients based on whether they used antidepressants. RESULTS: A total of 3174 women taking antidepressants (mean age 75.2 ± 6.4) were matched with 3174 women not taking antidepressants (mean age 75.4 ± 6.7). Antidepressant use was associated with a significantly increased risk of cognitive impairment (hazard ratio [HR]: 1.33, 95%; confidence interval [CI]: 1.18-1.48). Additionally, we found that older women without a history of depression or anxiety who use antidepressants have a higher risk of developing cognitive impairment than those who did not use antidepressants (HR: 1.53, 95%; CI: 1.34-1.75 and HR: 1.39, 95%; CI: 1.23-1.56, respectively). Subgroup analysis showed that the use of non-tricyclic antidepressants (TCAs) was associated with a higher risk of cognitive impairment. CONCLUSION: We found that non-TCA antidepressant use in older women with breast cancer was associated with a higher risk of cognitive impairment. This association was also observed among older women without depression or anxiety who used antidepressants.

Western diet-induced obesity disrupts the diurnal rhythmicity of hippocampal core clock gene expression in a mouse model.

Western diet (WD) feeding disrupts core clock gene expression in peripheral tissues and contributes to WD-induced metabolic disease. The hippocampus, the mammalian center for memory, is also sensitive to WD feeding, but whether the WD disrupts its core clock is unknown. To this end, male mice were maintained on a WD for 16 weeks and diurnal metabolism, gene expression and memory were assessed. WD-induced obesity disrupted the diurnal rhythms of whole-body metabolism, markers of inflammation and hepatic gene expression, but did not disrupt diurnal expression of hypothalamic Bmal1, Npas2 and Per2. However, all measured core clock genes were disrupted in the hippocampus after WD feeding and the expression pattern of genes implicated in Alzheimer's disease and synaptic function were altered. Finally, WD feeding disrupted hippocampal memory in a task- and time-dependent fashion. Our results implicate WD-induced alterations in the rhythmicity of hippocampal gene expression in the etiology of diet-induced memory deficits.

Neuronal CXCL10/CXCR3 Axis Mediates the Induction of Cerebral Hyperexcitability by Peripheral Viral Challenge.

Peripheral infections can potently exacerbate neuropathological conditions, though the underlying mechanisms are poorly understood. We have previously demonstrated that intraperitoneal (i.p.) injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC) induces a robust generation of CXCL10 chemokine in the hippocampus. The hippocampus also features hyperexcitability of neuronal circuits following PIC challenge. The present study was undertaken to determine the role of CXCL10 in mediating the development of hyperexcitability in response to PIC challenge. Briefly, young female C57BL/6 mice were i.p. injected with PIC, and after 24 h, the brains were analyzed by confocal microscopy. CXCL10 staining of neuronal perikarya and a less intense staining of the neuropil was observed in the hippocampus and cortex. CXCL10 staining was also evident in a subpopulation of astrocytes, whereas microglia were CXCL10 negative. CXCR3, the cognate receptor of CXCL10 was present exclusively on neurons, indicating that the CXCL10/CXCR3 axis operates through an autocrine/paracrine neuronal signaling. Blocking cerebral CXCR3 through intracerebroventricular injection of a specific inhibitor, AMG487, abrogated PIC challenge-induced increase in basal synaptic transmission and long-term potentiation (LTP), as well as the reduction of paired-pulse facilitation (PPF), in the hippocampus. The PIC-mediated abolishment of hippocampal long-term depression (LTD) was also restored after administration of AMG487. Moreover, CXCR3 inhibition attenuated seizure hypersensitivity induced by PIC challenge. The efficacy of AMG487 strongly strengthens the notion that CXCL10/CXCR3 axis mediates the induction of cerebral hyperexcitability by PIC challenge.

Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.

AIMS: This study investigated the neurotoxic effects of prenatal alcohol and nicotine exposure in the cortex and hippocampus of rodents. MAIN METHODS: Behavioral alterations, electrophysiological changes, and biochemical markers associated with cholinergic neurotransmission, neural oxidative stress, mitochondrial function, and apoptosis were evaluated. KEY FINDINGS: Prenatal alcohol exposure induced the generation of ROS, nitrite and lipid peroxide, decreased mitochondrial Complex-I and IV activities, increased Caspase-1 and 3 activities, had no effect on cholinergic neurotransmission, increased expression of PSD-95, decreased LTP and decreased performance on spatial memory tasks. However, nicotine exposure, in addition to alcohol exposure, was found to mitigate the negative effects of alcohol alone on ROS generation and spatial memory task performances. Furthermore, we also studied the role of ILK in prenatal alcohol and nicotine exposure. SIGNIFICANCE: Prenatal Smoking and/or drinking is a major health concern around the world. Thus, our current study may lead to better insights into the molecular mechanisms of fetal alcohol and nicotine exposure on the developing offspring.

Adiponectin Knockout Mice Display Cognitive and Synaptic Deficits.

Adiponectin is an adipokine that has recently been under investigation for potential neuroprotective effects in various brain disorders including Alzheimer's disease, stroke, and depression. Adiponectin receptors (AdipoR1 and AdipoR2) are found throughout various brain regions, including the hippocampus. However, the role of these receptors in synaptic and cognitive function is not clear. Therefore, the goal of the current study was to evaluate synaptic and cognitive function in the absence of adiponectin. The current study utilized 12-month-old adiponectin knockout (APN-KO) mice and age-matched controls to study cognitive and hippocampal synaptic alterations. We determined that AdipoR1 and AdipoR2 are present in the synaptosome, with AdipoR2 displaying increased presynaptic vs. postsynaptic localization, whereas AdipoR1 was enriched in both the presynaptic and postsynaptic fractions. APN-KO mice displayed cognitive deficits in the novel object recognition (NOR) and Y-maze tests. This was mirrored by deficits in long-term potentiation (LTP) of the hippocampal Schaefer collateral pathway in APN-KO mice. APN-KO mice also displayed a reduction in basal synaptic transmission and an increase in presynaptic release probability. Deficits in LTP were rescued through hippocampal slice incubation with the adiponectin receptor agonist, AdipoRon, indicating that acute alterations in adiponectin receptor signaling influence synaptic function. Along with the deficits in LTP, altered levels of key presynaptic and postsynaptic proteins involved in glutamatergic neurotransmission were observed in APN-KO mice. Taken together, these results indicate that adiponectin is an important regulator of cognition and synaptic function in the hippocampus. Future studies should examine the role of specific adiponectin receptors in synaptic processes.

Hippocampal Genetic Knockdown of PPARδ Causes Depression-Like Behaviors and Neurogenesis Suppression.

BACKGROUND: Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Our previous study showed that hippocampal peroxisome proliferator-activated receptor δ (PPARδ) overexpression displays antidepressive effect and enhances hippocampal neurogenesis during chronic stress. Herein, we further extended our curiosity to investigate whether downregulating PPARδ could cause depressive-like behaviors through downregulation of neurogenesis. METHODS: Stereotaxic injection of lentiviral vector, expressing short hairpin RNA complementary to the coding exon of PPARδ, was done into the bilateral dentate gyri of the hippocampus, and the depression-like behaviors were observed in mice. Additionally, hippocampal neurogenesis, brain-derived neurotrophic factor and cAMP response element-binding protein were measured both in vivo and in vitro. RESULTS: Hippocampal PPARδ knockdown caused depressive-like behaviors and significantly decreased neurogenesis, neuronal differentiation, levels of mature brain-derived neurotrophic factor and phosphorylated cAMP response element-binding protein in the hippocampus. In vitro study further confirmed that PPARδ knockdown could inhibit proliferation and differentiation of neural stem cells. Furthermore, these effects were mimicked by repeated systemic administration of a PPARδ antagonist, GSK0660 (1 or 3 mg/kg i.p. for 21 d). CONCLUSIONS: These findings suggest that downregulation of hippocampal PPARδ is associated with depressive behaviors in mice through an inhibitory effect on cAMP response element-binding protein/brain-derived neurotrophic factor-mediated adult neurogenesis in the hippocampus, providing new insights into the pathogenesis of depression.

Protective effects of tauroursodeoxycholic acid on lipopolysaccharide-induced cognitive impairment and neurotoxicity in mice.

Accumulating evidence has shown that tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of neurological diseases. However, whether TGR5 agonist TUDCA can improve lipopolysaccharide (LPS)-induced cognitive impairment in mice is less clear. Using a model of cognitive impairment with LPS (2.0 µg) we investigated the effects of TUDCA (200 or 400 µg) on cognitive dysfunction and neurotoxicity in mice. Both Morris water maze and Y-maze avoidance tests showed that TUDCA treatment significantly alleviated LPS-induced behavioral impairments. More importantly, we found that TUDCA treatment reversed TGR5 down-regulation, prevented neuroinflammation via inhibiting NF-κB signaling in the hippocampus of LPS-treated mice. Additionally, TUDCA treatment decreased LPS-induced apoptosis through decreasing TUNEL-positive cells and the overexpression of caspase-3, increasing the ratio of Bcl-2/Bax. TUDCA treatment also ameliorated synaptic plasticity impairments by increasing the ratio of mBDNF/proBDNF, the number of dendritic spines and the expression of synapse-associated proteins in the hippocampus. Our results indicated that TUDCA can improve cognitive impairment and neurotoxicity induced by LPS in mice, which is involved in TGR5-mediated NF-κB signaling.

Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation.

Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.