GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus

Helm, Katherine A.; Haberman, Rebecca P.; Dean, Shannon L.; Hoyt, Eileen C.; Melcher, Thorsten; Lund, P. Kay; Gallagher, Michela

doi:10.1016/j.neuropharm.2005.01.019

Cited by 104 publications

(76 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additionally, this structure is required for contextual conditioning, and evidence suggest that inactivation of hippocampal GABA B receptors improves spatial working memory (41). In the present study, hippocampal GABA B1b mRNA is reduced in L. rhamnosus (JB-1)-fed mice, which is consistent with an enhanced memory consolidation in the fear conditioning test and further suggests that the changes in hippocampal gene expression induced by the Lactobacillus could in part account for these differences in behavior.…”

Section: Discussionsupporting

confidence: 78%

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Bravo¹,

Forsythe

Chew

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

3,127

2,512

View full text Add to dashboard Cite

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA B1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA Aα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABA Aα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety-and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stressrelated disorders such as anxiety and depression.brain-gut axis | irritable bowel syndrome | probiotic | fear conditioning | cognition T here is increasing evidence suggesting an interaction between the intestinal microbiota, the gut, and the central nervous system (CNS) in what is recognized as the microbiome-gut-brain axis (1-4). Studies in rodents have implicated dysregulation of this axis in functional bowel disorders, including irritable bowel syndrome. Indeed, visceral perception in rodents can be affected by alterations in gut microbiota (5). Moreover, it has been shown that the absence and/or modification of the gut microflora in mice affects the hypothalamic-pituitary-adrenal (HPA) axis response to stress (6, 7) and anxiety behavior (8, 9), which is important given the high comorbidity between functional gastrointestinal disorders and stress-related psychiatric disorders, such as anxiety and depression (10). In addition, pathogenic bacteria in rodents can induce anxiety-like behaviors, which are mediated via vagal afferents (9, 11).GABA is the main inhibitory neurotransmitter of the CNS, the effects of which are mediated through two major classes of receptors-the ionotropic GABA A receptors, which exist as a number of subtypes formed by the coassembly of different subunits (α, β, and γ subunits; ref. 12), and the GABA B receptors, which are G protein coupled and consist of a heterodi...

show abstract

Section: Discussionsupporting

confidence: 78%

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Bravo¹,

Forsythe

Chew

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

3,127

2,512

View full text Add to dashboard Cite

show abstract

“…STAT3 Activation and Role in TNF␣-induced TIMP-1 ExpressionElectromobility shift assays were used to monitor STAT3 activation by TNF␣ as previously described (40). Nuclear protein extracts were isolated from serum-deprived intestinal myofibroblasts treated with 5 ng/ml TNF␣ for 60 min.…”

Section: Erk1/2 Activation and Role In Tnf␣-induced Intestinalmentioning

confidence: 99%

Tumor Necrosis Factor (TNF) α Increases Collagen Accumulation and Proliferation in Intestinal Myofibroblasts via TNF Receptor 2

Theiss¹,

Simmons²,

Jobin

et al. 2005

Journal of Biological Chemistry

203

136

View full text Add to dashboard Cite

Intestinal fibrosis is an incurable complication of Crohn's disease involving increased numbers of collagen-producing myofibroblasts. Tumor necrosis factor (TNF) ␣ has defined proinflammatory roles in Crohn's disease but its role in fibrosis is unclear. We tested the hypothesis that TNF␣ increases collagen accumulation and proliferation in intestinal myofibroblasts and has additive effects in combination with insulin-like growth factor (IGF) Fibrosis is a major and serious complication of Crohn's disease, an incurable, chronic inflammatory disease of the gastrointestinal tract. Fibrosis results from an imbalance between synthesis and degradation of collagen and other extracellular matrix components, ultimately leading to increased net matrix accumulation within the bowel wall. Fibrosis is thought to be an overactive, irreversible wound-healing response to chronic inflammation (1) and can lead to the serious complications of stricture, bowel narrowing and/or obstruction. In the normal intestine, subepithelial myofibroblasts, and fibroblasts in the submucosa, intermuscle connective tissue of the muscularis propria, and serosa are the primary sites of collagen mRNA and protein expression (2, 3). In intestine of patients with Crohn's disease, myofibroblasts are increased in number in all bowel layers and colocalize with sites of type I collagen mRNA expression and collagen deposition (2). These results suggest that myofibroblasts are cellular mediators of intestinal fibrosis in Crohn's disease. Wound healing and fibrosis in other organs also involves myofibroblasts (4 -6).ITumor necrosis factor ␣ (TNF␣) 2 is a central mediator of chronic inflammatory diseases including Crohn's disease, as evidenced from clinical studies reporting a dramatic improvement in Crohn's patients treated with infliximab (Remicade; Centocore, Inc.), a neutralizing monoclonal antibody against TNF␣ (7, 8). The role of TNF␣ in inflammation-induced fibrosis appears complex because available evidence suggests that TNF␣ regulates collagen synthesis in a tissue-specific manner. In hepatic stellate cells during liver injury, several studies indicate anti-fibrogenic actions of TNF␣ via inhibition of collagen ␣1(I) gene expression (9 -12). However, increasing evidence indicates TNF␣ as a mediator of inflammation-induced fibrosis in other systems. Mice deficient in either the 55-(TNFR1) or 75-kDa (TNFR2) TNF receptor show reduced experimentally induced pulmonary fibrosis (13) or renal fibrosis (14). The reduced pulmonary fibrosis in TNF receptor null mice occurred despite similar increases in type I collagen gene expression as wild-type mice, but was accompanied by attenuated induction of tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA (13). TIMP-1 is an inhibitor of matrix metalloproteinases (MMPs) that cleave various components of the extracellular matrix and therefore reduces collagen degradation. These findings in TNFR null mice suggest that TNF␣ normally plays a role in up-regulation of TIMP-1 during lung injury and may promote fibrosis by i...

show abstract

“…69 These clinical findings are supported by preclinical studies showing that the GABA B receptor antagonist displays pronounced cognitive enhancing effects in rats involved in different learning tasks. 70 These behavioral observations are paralleled by molecular experiments revealing that SGS742 significantly increased BDNF expression in frontal cortex and hippocampus. The neurotrophin expression was markedly increased when measured 24 h following the treatment, suggesting a putative molecular mechanism through which SGS742 might affect cognitive processes.…”

Section: Gaba-b Antagonistsmentioning

confidence: 82%

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

2005

View full text Add to dashboard Cite

Finding an effective treatment for chronic neurodegenerative disorders still represents an unmet goal. There is considerable evidence that such disorders represent a combination of genetic determinants and failure of neuroprotective mechanisms sparking a wider degree of interest in shedding light on the cellular changes responsible for these devastating disorders. Because of their role in survival or differentiation of developing neurons, as well as the recent discovery of their importance in regulating synaptic plasticity during adulthood, neurotrophic factors have been suggested as essential contributors of the etiology of neurodegenerative disorders. Alzheimer's disease (AD) is a complex, chronic, devastating disease that affects a high percentage of the population over 65 years of age. This review will focus on different pharmacological interventions that are currently in use or drugs under development, narrowing the therapeutic agents to those that interfere with the expression of the trophic factor brain-derived neurotrophic factor (BDNF), a molecule playing a pivotal role in synaptic plasticity and cognition. From these findings, it appears clear that BDNF is implicated in the mechanism of action of drugs that improve cognitive deficits in animal models of AD and in AD patients.

show abstract

GABAB receptor antagonist SGS742 improves spatial memory and reduces protein binding to the cAMP response element (CRE) in the hippocampus

Cited by 104 publications

References 27 publications

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Tumor Necrosis Factor (TNF) α Increases Collagen Accumulation and Proliferation in Intestinal Myofibroblasts via TNF Receptor 2

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

Contact Info

Product

Resources

About