Polarization to M1-type microglia in the hippocampus is involved in depression-like behavior in a mouse model of olfactory dysfunction.

Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO4) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO4-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO4-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO4-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.

Effect of Globin Digests on Physical Fatigue in Mice.

Globin digest (GD) inhibits dietary hypertriglyceridemia; however, its effects on physical fatigue remain unknown. Therefore, this study aimed to investigate the potential anti-fatigue effects of GD. Repeated administration of GD and valine (Val)-Val-tyrosine (Tyr)-proline (Pro), a component of GD, for five days prevented the forced walking-induced decrease in locomotion. Furthermore, GD treatment reversed the forced walking-induced increase in blood lactate levels in mice and increased phosphorylated AMP-activated protein kinase (p-AMPK) in the soleus muscle, suggesting that the anti-fatigue effect of GD involves AMPK activation in the soleus muscle through reduced blood lactate.

Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice.

Angiotensin (Ang)-converting-enzyme (ACE) 2 converts Ang II into Ang (1-7), which in turn acts on MAS receptors (ACE2/Ang (1-7)/MAS receptors pathway). This pathway has neuroprotective properties, making it a potential therapeutic target for psychiatric disorders such as depression. Thus, we examined the effects of diminazene aceturate (DIZE), an ACE2 activator, on depressive-like behavior using behavioral, pharmacological, and biochemical assays. To determine whether DIZE or Ang (1-7) produce antidepressant-like effects, we measured the duration of immobility of mice in the tail suspension test following their intracerebroventricular administration. Next, we measured the levels of ACE2 activation in the cerebral cortex, prefrontal cortex, hippocampus, and amygdala after DIZE injection, and examined which cell types, including neurons, microglia, and astrocytes, express ACE2 in the hippocampus using immunofluorescence. Administration of DIZE or Ang (1-7) significantly shortened the duration of immobility time in the tail suspension test, while this effect was inhibited by the co-administration of the MAS receptor antagonist A779. DIZE activated ACE2 in the hippocampus. ACE2 was localized to neurons, astrocytes, and microglia in the hippocampus. In conclusion, these results suggest that DIZE may act on ACE2-positive cells in the hippocampus where it increases the activity of ACE2, thereby enhancing signaling of the ACE2/Ang (1-7)/MAS receptor pathway and resulting in antidepressant-like effects.

Angiotensin-Related Peptides and Their Role in Pain Regulation.

Angiotensin (Ang)-generating system has been confirmed to play an important role in the regulation of fluid balance and blood pressure and is essential for the maintenance of biological functions. Ang-related peptides and their receptors are found throughout the body and exhibit diverse physiological effects. Accordingly, elucidating novel physiological roles of Ang-generating system has attracted considerable research attention worldwide. Ang-generating system consists of the classical Ang-converting enzyme (ACE)/Ang II/AT1 or AT2 receptor axis and the ACE2/Ang (1-7)/MAS1 receptor axis, which negatively regulates AT1 receptor-mediated responses. These Ang system components are expressed in various tissues and organs, forming a local Ang-generating system. Recent findings indicate that changes in the expression of Ang system components under pathological conditions are involved in the development of neuropathy, inflammation, and their associated pain. Here, we summarized the effects of changes in the Ang system on pain transmission in various organs and tissues involved in pain development process.

Peptides obtained by enzymatic decomposition of mackerel induce recovery from physical fatigue by enhancing the SIRT1-mediated antioxidant effect in the soleus muscle of mice.

Fatigue is a serious health problem, and long-term fatigue can lead to mental illnesses and accelerated aging. Oxidative stress, which causes excessive production of reactive oxygen species, is generally thought to increase during exercise and is an indicator of fatigue. Peptides obtained by enzymatic decomposition of mackerel (EMP) contain selenoneine, a strong antioxidant. Although antioxidants increase endurance, the effects of EMP on physical fatigue are unknown. The present study aimed to clarify this aspect. We investigated the effects of EMP on changes in locomotor activity, expression levels of silent mating type information regulation 2 homolog peroxisome 1 (SIRT1), proliferator-activated receptor-γ coactivator-1α (PGC1α), and antioxidative-related proteins including superoxide dismutase 1 (SOD1), SOD2, glutathione peroxidase 1, and catalase in the soleus muscle following EMP treatment before and/or after forced walking. Treatment with EMP before and after forced walking, and not only at one or another time point, improved the subsequent decrease in the locomotor activity and enhanced the levels of SIRT1, PGC1α, SOD1, and catalase expression in the soleus muscle of mice. Moreover, EX-527, a SIRT1 inhibitor, abolished these effects of EMP. Thus, we suggest that EMP combats fatigue by modulating the SIRT1/PGC1α/SOD1-catalase pathway.

Donepezil prevents olfactory dysfunction and α-synuclein aggregation in the olfactory bulb by enhancing autophagy in zinc sulfate-treated mice.

Alzheimer's disease is associated with marked olfactory dysfunction observed in the early stages. Clinical studies reported that acetylcholinesterase inhibitor donepezil (DNP) attenuated this deficit; however, the underlying mechanism remains unclear. Herein, we aimed to examine the effects and underlying mechanisms of DNP on olfactory deficits in zinc sulfate (ZnSO4) nasal-treated mice, which were used as a model of reversible olfactory impairment. We evaluated olfactory function using the buried food finding test and neurogenesis in the subventricular zone (SVZ) using immunohistochemistry. Finally, we measured the expression of doublecortin (DCX), neuronal nuclear antigen (NeuN), olfactory marker protein, tyrosine hydroxylase (TH), tryptophan hydroxylase 2, glutamic acid decarboxylase 67, p-α-synuclein (Ser129), α-synuclein, p-AMPK, p-p70S6 kinase (p70S6K) (Thr389), LC3 Ⅱ/Ⅰ, and p-p62 in the olfactory bulb (OB) by western blotting. On day 7 after treatment, ZnSO4-treated mice exhibited prolonged time to find the buried food, cell proliferation enhancement in the SVZ, increased NeuN, p-α-synuclein (Ser129), and α-synuclein levels, and decreased DCX and TH levels in the OB; except for TH, these changes normalized on day 14 after treatment. Repeated administration of DNP prevented the ZnSO4-induced changes on day 7 after treatment. Moreover, DNP increased p-AMPK and LC3 Ⅱ/Ⅰ, and decreased p-p70S6K and p-p62 (Ser351) levels in the OB, suggesting that DNP enhances autophagy in the OB. These findings indicate that DNP may help prevent olfactory dysfunction by autophagy that reduces α-synuclein aggregation via the AMPK/mTOC1 pathway.

Intracerebroventricular Administration of Dermorphin-Dynorphin Analogs Producing Antidepressant-Like Effects through Activation of µ1- and κ-Opioid Receptors in Mice.

The opioid system in the central nervous system regulates depressive-like behavior in animals. Opioid receptors and their endogenous ligands have been focused on as novel therapeutic targets for depression. We synthesized dermorphin (DRM)-dynorphin (DYN) analogs (DRM-DYN001-004) using the message-address concept concerning interactions with opioid receptors. It has previously been reported that DRM-DYN001, 003, and 004 have shown high affinities for µ- and κ-opioid receptors, whereas all analogs had a lower affinity for the δ-opioid receptor than for other receptors using a receptor binding assay. However, it remains unknown whether these analogs show antidepressant-like effects in mice. We examined the effects of DRM-DYN analogs on the duration of immobile behavior in a tail suspension test. Intracerebroventricular administration of DRM-DYN001 in mice shortened the duration of immobile behavior, but did not affect locomotion. The DRM-DYN001-induced antidepressant-like effect was inhibited by co-administration of naloxone (non-selective opioid receptor antagonist), naloxonazine (selective µ1-opioid receptor antagonist), or nor-BNI (κ-opioid receptor antagonist), but not naltrindole (δ-opioid receptor antagonist). These data suggest that DRM-DYN001 exerts an antidepressant-like effect via activation of the central µ1- and κ-opioid receptors in mice and may represent a new lead peptide for further investigation for the development of novel therapeutic approaches for depression.

Antidepressant Effect of Intracerebroventricularly Administered Deltorphin Analogs in the Mouse Tail Suspension Test.

Several studies have proposed δ opioid receptors as influential targets for developing novel antidepressants. Deltorphin (DLT) and deltorphin II (DLT-II) have high affinity and selectivity for δ opioid receptors; thus, it is likely that DLT analogs possess antidepressant-like effects. Based on this, we evaluated the effects of four DLT analogs (DLT-related synthetic peptides) on immobility behavior in the tail suspension test. Intracerebroventricular administration of DLT or [N-isobutyl-Gly6]DLT in mice significantly decreased immobile behavior. However, administration of DLT did not affect locomotor activity, whereas that of [N-isobutyl-Gly6]DLT significantly increased locomotion in mice. The effect of the shortened immobility time following DLT administration was counteracted by the administration of the selective δ1 opioid receptor antagonist 7-benzylidenenaltrexone, but not by the selective δ2 opioid receptor antagonist naltriben. These findings suggest that DLT has an antidepressant-like effect by activating the central δ1 opioid receptor in mice.

ERK5 inhibitor BIX02189 attenuates methamphetamine-induced hyperactivity by modulating microglial activation in the striatum.

Extracellular signal-regulated protein kinase 5 (ERK5) has various physiological functions. However, the physiological role of ERK5 in the treatment of mice with an illicit drug such as methamphetamine (METH) remains unknown. We revealed that mice treated with METH showed hyperactivity, and increased p-ERK5 and Iba1 (a microglia marker) levels in the striatum. Additionally, these changes were inhibited by pretreatment with the ERK5 inhibitor BIX02189. The results suggest that METH-induced hyperactivity is associated with the activation of microglia via p-ERK5 in the striatum. Thus, the ERK5 pathway components in the central nervous system are potential therapeutic targets for preventing METH addiction.

Antidepressant effects of Enterococcus faecalis 2001 through the regulation of prefrontal cortical myelination via the enhancement of CREB/BDNF and NF-κB p65/LIF/STAT3 pathways in olfactory bulbectomized mice.

A therapeutic strategy through the gut-brain axis has been proven to be effective in treatment for depression. In our previous study, we demonstrated that Enterococcus faecalis 2001 (EF-2001) prevents colitis-induced depressive-like behavior through the gut-brain axis in mice. More recently, we found that demyelination in the prefrontal cortex (PFC) was associated with depressive-like behavior in an animal model of major depressive disorder, olfactory bulbectomized (OBX) mice. The present study investigated the effects of EF-2001 on depressive-like behaviors in OBX mice and the underlying molecular mechanisms from the perspective of myelination in the PFC. OBX mice exhibited depressive-like behaviors in the tail-suspension, splash, and sucrose preference tests, and decreased myelin and paranodal proteins along with mature oligodendrocytes in the PFC. These behavioral and biochemical changes were all prevented by treatment with EF-2001. Further, EF-2001 treatment increased brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) in the PFC. Interestingly, an immunohistochemical analysis revealed enhanced phospho (p) -cAMP-responsive element binding protein (CREB) expression in neurons, p-nuclear factor-kappa B (NFκB) p65 (Ser536) expression in astrocytes, and p-signal transducer and activator of transcription 3 (STAT3) (Ty705) expression in mature oligodendrocytes in the PFC of OBX mice. From these results, we suggest that EF-2001 administration prevents depressive-like behaviors by regulating prefrontal cortical myelination via the enhancement of CREB/BDNF and NFκB p65/LIF/STAT3 pathways. Our findings strongly support the idea that a therapeutic strategy involving the gut microbiota may be a promising alternative treatment for alleviating symptoms of depression.

Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions.

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

Low Skeletal Muscle Mass Is Associated With Perioperative Neurocognitive Disorder Due To Decreased Neurogenesis in Rats.

BACKGROUND: Perioperative neurocognitive disorder (PND) is a postsurgical complication associated with neuroinflammation and impaired hippocampal neurogenesis, in which brain-derived neurotrophic factor (BDNF) plays a key role. Sarcopenia refers to age-related muscle loss that causes cognitive decline, muscle atrophy, and postoperative delirium. Rats with tail suspension (TS) were used to represent a low-activity model, which involves decreased hind limb function by TS. This hind limb unloading by TS can induce sarcopenia in 2 weeks. However, the relationship between PND and muscle atrophy is unclear. In this experiment, we investigated whether preoperative muscle atrophy induced by TS would affect neurogenesis and accelerate PND in rats. METHODS: Sixty 21-week-old rats were assigned to 4 groups: the TS group, the TS with surgery (TS + S) group, the control group, and the control with surgery (control + S) group. After the abdominal manipulation under 3% sevoflurane anesthesia, cognitive function was assessed using the Morris water maze test and a fear-conditioning test. Neurogenesis was evaluated by checking BDNF secretion and immunohistochemical staining in the hippocampus. RESULTS: The TS + S group showed impaired swimming latency (difference of means = 12.4 versus control + S; 95% confidence interval [CI], 2.0-22.7; P = .016) (difference of means = 15.2 versus TS; 95% CI, 0.4-30.1; P = .043) and path length (difference of means = 147.8 versus control + S; 95% CI, 20.7-274.9; P = .020) in the maze test and cued fear memory (difference of means = -26.0 versus TS; 95% CI, -46.4 to -5.6; P = .006) (difference of means = -22.3 versus control + S; 95% CI, -42.7 to -1.9; P = .026) in the fear-conditioning test. The postoperative levels of BDNF in the TS + S and TS groups were reduced compared with the other groups (P = .002). The number of neural precursors in the dentate gyrus was significantly lower in the TS + S group (P < .001). CONCLUSIONS: We observed that preoperative hind limb muscle atrophy, indicated by TS, was associated with an increased occurrence of PND through the reduction in BDNF and neurogenesis after abdominal surgery in young adult rats. Therefore, we concluded that preoperative low skeletal muscle mass can induce PND due to impaired postoperative neurogenesis. Our findings might indicate that low-cost perioperative interventions, such as preoperative exercise, is beneficial to preventing PND.

Angiotensin (1-7) Attenuates the Nociceptive Behavior Induced by Substance P and NMDA via Spinal MAS1.

The intrathecal (i.t.) injection of substance P (SP) and N-methyl-D-aspartate (NMDA) induce transient nociceptive response by activating neurokinin (NK) 1 and NMDA receptors, respectively. We have recently reported that angiotensin (Ang) (1-7), an N-terminal fragment of Ang II, could alleviate several types of pain including neuropathic and inflammatory pain by activating spinal MAS1. Here, we investigated whether Ang (1-7) can inhibit the SP- and NMDA-induced nociceptive response. The nociceptive response induced by an i.t. injection of SP or NMDA was assessed by measuring the duration of hindlimb scratching directed toward the flank, biting and/or licking of the hindpaw or the tail for 5 min. Localization of MAS1 and either NK1 or NMDA receptors in the lumbar superficial dorsal horn was determined by immunohistochemical observation. The nociceptive response induced by SP and NMDA was attenuated by the i.t. co-administration of Ang (1-7) (0.03-3 pmol) in a dose-dependent manner. The inhibitory effects of Ang (1-7) (3 pmol) were attenuated by A779 (100 pmol), a MAS1 antagonist. Moreover, immunohistochemical analysis showed that spinal MAS1 co-localized with NK1 receptors and NMDA receptors on cells in the dorsal horn. Taken together, the i.t. injection of Ang (1-7) attenuated the nociceptive response induced by SP and NMDA via spinal MAS1, which co-localized with NK1 and NMDA receptors. Thus, the spinal Ang (1-7)/MAS1 pathway could represent a therapeutic target to effectively attenuate spinal pain transmission caused by the activation of NK1 or NMDA receptors.

Activation of cholinergic system partially rescues olfactory dysfunction-induced learning and memory deficit in mice.

Deficits in olfaction are associated with neurodegenerative disorders such as Alzheimer's disease. A recent study reported that intranasal zinc sulfate (ZnSO4)-treated mice show olfaction and memory deficits. However, it remains unknown whether olfaction deficit-induced learning and memory impairment is associated with the cholinergic system in the brain. In this study, we evaluated olfactory function by the buried food find test, and learning and memory function by the Y-maze and passive avoidance tests in ZnSO4-treated mice. The expression of choline acetyltransferase (ChAT) protein in the olfactory bulb (OB), prefrontal cortex, hippocampus, and amygdala was assessed by western blotting. Moreover, we observed the effect of the acetylcholinesterase inhibitor physostigmine on ZnSO4-induced learning and memory deficits. We found that intranasal ZnSO4-treated mice exhibited olfactory dysfunction, while this change was recovered on day 14 after treatment. Both short-term and long-term learning and memory were impaired on days 4 and 7 after treatment with ZnSO4, whereas the former, but not the latter, was recovered on day 14 after treatment. A significant correlation was observed between olfactory function and short-term memory, but not long-term memory. Treatment with ZnSO4 decreased the ChAT level in the OB on day 4, and increased and decreased the ChAT levels in the OB and hippocampus on day 7, respectively. Physostigmine improved the ZnSO4-induced deficit in short-term, but not long-term, memory. Taken together, the present results suggest that short-term memory may be closely associated with olfactory function via the cholinergic system.

Scabronine G Methyl Ester Improves Memory-Related Behavior and Enhances Hippocampal Cell Proliferation and Long-Term Potentiation via the BDNF-CREB Pathway in Olfactory Bulbectomized Mice.

A previous study reported that scabronine G methyl ester (SG-ME) potentially enhances the in vitro secretion of neurotrophic factors such as nerve growth factor via the protein kinase C (PKC)-ζ pathway. However, it remains unknown whether SG-ME can improve cognitive dysfunctions in olfactory bulbectomized (OBX) mice. To address this question, we evaluated SG-ME-treated and untreated OBX mice in a passive avoidance test. We also investigated potential effects of SG-ME on several parameters: cell proliferation and cAMP response element-binding protein (CREB) phosphorylation in the hippocampal dentate gyrus by immunohistochemistry, brain-derived neurotrophic factor (BDNF) levels in the hippocampus by Western blotting, p-CREB levels in the hippocampus by MapAnalyzer, and long-term potentiation (LTP) by electrophysiology. On the 14th day after surgery OBX mice showed altered passive avoidance and decreases in both cell proliferation and long-term potentiation in the hippocampus, while these changes were reversed by SG-ME (20 µg/mouse) 24 h after the treatment. The improvement in memory deficits was prevented when SG-ME was co-administeredwith either zeta inhibitory peptide (PKC-ζ inhibitor), anti-BDNF antibody, ANA-12 (TrkB antagonist), U0126 (MEK inhibitor), H-89 (PKA inhibitor), LY294002 (PI3K inhibitor) or KN-93 (CaMKII inhibitor). We found that SG-ME enhanced brain-derived neurotrophic factor and p-CREB levels in the hippocampus while p-CREB was localized in neurons, but not in astrocytes nor microglial cells. These findings revealed the potential of SG-ME in improving memory impairments by enhancing cell proliferation and LTP via activation of the BDNF/CREB signaling pathway in neurons.

Dopamine D2 receptor supersensitivity in the hypothalamus of olfactory bulbectomized mice.

Olfactory bulbectomy (OBX) in rodents induces neurochemical and behavioral changes similar to those observed in individuals with depressive disorders. Our previous study suggested that OBX alters dopaminergic function in the striatum of mice; however, the effects on dopaminergic function in the hypothalamus is unknown. Therefore, in this study we examined dopaminergic system changes in the hypothalamus after OBX. Mice were administrated either the nonselective dopamine (DA) agonist apomorphine or the selective D2 agonist quinelorane, or pretreated with the selective D1 antagonist SCH23390 in combination with the selective D2 antagonist sulpiride or D3 antagonist SB277011A. Body temperature, which is regulated by the hypothalamic dopaminergic system, was monitored to evaluate changes in the dopaminergic system of the hypothalamus. DA D2 receptor (D2DR), tyrosine hydroxylase (TH), and phosphorylated (p)- DA- and cAMP-regulated phosphoprotein-32 (DARPP-32) levels in the hypothalamus were evaluated by western blotting. OBX mice exhibited significantly enhanced apomorphine-induced or quinelorane-induced hypothermia. The apomorphine-induced hypothermic response was reversed by the administration of sulpiride, but not SCH23390 or SB277011A. Moreover, TH and p-DARPP-32 levels were reduced and D2DR increased in the hypothalamus of OBX mice. These findings revealed that the OBX mice display enhanced DA receptor responsiveness associated with the hypothalamus, which may relate to some of the behavioral and neurochemical alterations reported in this animal model. Identification of changes in the hypothalamic dopaminergic system of OBX mice may provide useful information for the development of novel antidepressant treatments.

Antidepressant effect of BE360, a new selective estrogen receptor modulator, activated via CREB/BDNF, Bcl-2 signaling pathways in ovariectomized mice.

We have previously reported that the carborane compound BE360, a novel selective estrogen receptor modulator, has a therapeutic potential against dementia. This study aimed to explore the effects and underlying mechanisms of BE360 on depression-like behaviors in ovariectomized (OVX) mice subjected to subchronic stress, which are postmenopausal depression models. BE360 was subcutaneously administrated using a mini-osmotic pump, for 2 weeks. Depression-like behaviors were evaluated using the forced swimming test. Neurogenesis in the hippocampal dentate gyrus (DG) was measured by analyzing cells expressing doublecortin (DCX) following 5-bromo-2'-deoxyuridine (BrdU) uptake. The levels of phosphorylated cyclic-AMP response element-binding protein (p-CREB), brain-derived neurotrophic factor (BDNF), and Bcl-2 were measured using immunohistochemistry or immunoblotting. Depression-like behaviors in OVX + Stress-exposed mice improved after chronic treatment with BE360. BE360 treatment in OVX + Stress-exposed mice increased p-CREB, BDNF, and Bcl-2 expressions in the hippocampus. Immunohistochemistry showed that the number of BrdU/DCX double-positive cells in the DG of the hippocampus, which decreased significantly in OVX + Stress-exposed mice, increased after subchronic treatment with BE360. The present study demonstrates that BE360 exerts antidepressant effects via hippocampal neurogenesis, potentially activated through CREB/BDNF, Bcl-2 signaling pathways. These results indicate that BE360 may have therapeutic potential against postmenopausal depression.

Antidementia effects of Enterococcus faecalis 2001 are associated with enhancement of hippocampal neurogenesis via the ERK-CREB-BDNF pathway in olfactory bulbectomized mice.

Our previous study showed that Enterococcus faecalis 2001 (EF-2001) suppresses colitis-induced depressive-like behavior through the enhancement of hippocampal neurogenesis in mice. In the present study, we investigated the effect of EF-2001 on the cognitive behavior of olfactory bulbectomized (OBX) mice and its molecular mechanisms. The OBX-induced cognitive dysfunction was significantly suppressed by EF-2001. Moreover, EF-2001 also recovered the reductions in p-ERK1/2, p-CREB, BDNF and DCX levels and in neurogenesis observed in the hippocampus of OBX mice. These results suggest that EF-2001-induced antidementia effects are associated with enhanced hippocampal neurogenesis through the ERK-CREB-BDNF pathway.

Liver hydrolysate prevents depressive-like behavior in an animal model of colitis: Involvement of hippocampal neurogenesis via the AMPK/BDNF pathway.

Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric pathology, including anxiety and depression. The dextran sulfate sodium (DSS)-treated mouse is a well-characterized animal model of colitis that exhibits IBD-like and depressive-like changes. A recent study found that phosphorylated (p-) adenosine monophosphate-activated protein kinase (AMPK) was associated with anti-inflammatory and antidepressant effects. Our previous research in an animal model of major depression suggests that liver hydrolysate (LH) has an antidepressant effect and combats physical fatigue by enhancement via the hippocampal or peripheral p-AMPK pathway. In this study, we examined whether or not LH has antidepressant and anti-inflammatory effects in mice with DSS-induced changes. We evaluated colon inflammation in DSS-treated mice and used the tail suspension and forced swimming tests to confirm whether or not LH prevents IBD-like symptoms and depressive-like behavior. Hippocampal expression of AMPK, brain-derived neurotrophic factor (BDNF), doublecortin, and neuronal nuclear antigen proteins was assessed by Western blotting. Hippocampal neurogenesis and morphometric changes in the microglia and astrocytes were examined by immunohistochemistry. DSS-treated mice showed IBD-like pathology and depressive-like behavior, a reduction in the hippocampal neuronal nuclear antigen level and neurogenesis, and increased hippocampal activation of microglia and astrocytes. These changes were reversed by LH. DSS-treated mice showed enhanced hippocampal expression of p-AMPK and BDNF after administration of LH. LH prevented depressive-like behavior by enhancing hippocampal neurogenesis through the AMPK/BDNF pathway and anti-neuroinflammation in the hippocampus. LH may be a therapeutic option for patients with IBD and depression.

Liver hydrolysate improves depressive-like behavior in olfactory bulbectomized mice: Involvement of hippocampal neurogenesis through the AMPK/BDNF/CREB pathway.

Recently, we has reported that AMPK activator has antidepressant effect. Previous our study suggested that liver hydrolysate (LH) activated adenosine monophosphate-activated protein kinase (AMPK) in periphery. However, the effect of LH on depression is unclear. Therefore, we examines whether LH has antidepressant effect on olfactory bulbectomized (OBX) mice. OBX mice showed depressive-like behavior in tail-suspension test and reduction of hippocampal neurogenesis, while these changes were reversed by LH. LH enhanced hippocampal phosphate-AMPK, brain-derived neurotrophic factor (BDNF) and phosphate-cyclic adenosine monophosphate response element-binding protein (CREB) in OBX mice. These data indicate that LH may produce antidepressant effects via hippocampal AMPK/BDNF/CREB signaling.