The effects of the ethanol extract of Cordia myxa leaves on the cognitive function in mice.

BACKGROUND: Cordia myxa L. (Boraginaceae) is widely distributed in tropical regions and it's fruits, leaves and stem bark have been utilized in folk medicine for treating trypanosomiasis caused by Trypanosoma cruzi. A population-based study showed that T. cruzi infection is associated with cognitive impairments. Therefore, if C. myxa has ameliorating activities on cognitive function, it would be useful for both T. cruzi infection and cognitive impairments. METHODS: In this study, we evaluated the effects of an ethanol extract of leaves of C. myxa (ELCM) on memory impairments and sensorimotor gating deficits in mice. The phosphorylation level of protein was observed by the Western blot analysis. RESULTS: The administration of ELCM significantly attenuated scopolamine-induced cognitive dysfunction in mice, as measured by passive avoidance test and novel object recognition test. Additionally, in the acoustic startle response test, we observed that the administration of ELCM ameliorated MK-801-induced prepulse inhibition deficits. We found that these behavioral outcomes were related with increased levels of phosphorylation phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK-3ß) in the cortex and extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus by western blot analysis. CONCLUSIONS: These results suggest that ELCM would be a potential candidate for treating cognitive dysfunction and sensorimotor gating deficits observed in individuals with neurodegenerative diseases.

4-Methoxycinnamic acid attenuates schizophrenia-like behaviors induced by MK-801 in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Scrophularia buergeriana has been used for traditional medicine as an agent for reducing heat in the blood and for nourishing kidney 'Yin'. Therefore, S. buergeriana might be a potential treatment for mental illness, especially schizophrenia, which may be attenuated by supplying kidney Yin and reducing blood heat. In a pilot study, we found that S. buergeriana alleviated sensorimotor gating dysfunction induced by MK-801. AIM OF THE STUDY: In the present study, we attempted to reveal the active component(s) of S. buergeriana as a candidate for treating sensorimotor gating dysfunction, and we identified 4-methoxycinnamic acid. We explored whether 4-methoxycinnamic acid could affect schizophrenia-like behaviors induced by hypofunction of the glutamatergic neurotransmitter system. MATERIALS AND METHODS: Mice were treated with 4-methoxycinnamic acid (3, 10, or 30 mg/kg, i.g.) under MK-801-induced schizophrenia-like conditions. The effect of 4-methoxycinnamic acid on schizophrenia-like behaviors were explored using several behavioral tasks. We also used Western blotting to investigate which signaling pathway(s) is involved in the pharmacological activities of 4-methoxycinnamic acid. RESULTS: 4-Methoxycinnamic acid ameliorated MK-801-induced prepulse inhibition deficits, social interaction disorders and cognitive impairment by regulating the phosphorylation levels of PI3K, Akt and GSK-3ß signaling in the prefrontal cortex. And there were no adverse effects in terms of catalepsy and motor coordination impairments. CONCLUSION: Collectively, 4-methoxycinnamic acid would be a potential candidate for treating schizophrenia with fewer adverse effects, especially the negative symptoms and cognitive dysfunctions.

The effect of fecal microbiota transplantation on autistic-like behaviors in Fmr1 KO mice.

The importance of alterations in bidirectional communication between gut and brain has become obvious in neuropsychiatric disorders. Gastrointestinal (GI) disturbances are very common in autism spectrum disorders (ASD), and the GI microbiota profiles in children with ASD are significantly different from those in the general population. Fragile X syndrome (FXS) is an inheritable developmental disability in humans, and patients with FXS exhibit autistic behaviors such as mental retardation and impaired social communication or interaction. We hypothesized that an increase in specific gut microbiota by fecal microbiota transplantation (FMT) would mitigate autistic-like behaviors. To test this hypothesis, we measured the effects of FMT from normal mice to Fmr1 KO mice on autistic-like behaviors using several behavioral tests. Because the amounts of A. muciniphila in Fmr1 KO mice was very low, we assessed A. muciniphila population, tested the expression of MUC2, and analyzed goblet cells in the gut after the FMT. We found that FMT ameliorated autistic-like behaviors, especially memory deficits and social withdrawal, and we observed that the levels of A. muciniphila were normalized to wild-type levels. In addition, FMT attenuated the increased levels of TNFα and Iba1 in the brains of Fmr1 KO mice. These results suggest that FMT could be a useful tool for the treatments of cognitive deficits and social withdrawal symptoms observed in FXS or ASD because it increases the population of A. muciniphila and decreases TNFα and Iba1 levels.

Green tea extract containing enhanced levels of epimerized catechins attenuates scopolamine-induced memory impairment in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Green tea has been used as a traditional medicine to control brain function and digestion. Recent works suggest that drinking green tea could prevent cognitive function impairment. During tea manufacturing processes, such as brewing and sterilization, green tea catechins are epimerized. However, the effects of heat-epimerized catechins on cognitive function are still unknown. To take this advantage, we developed a new green tea extract, high temperature processed-green tea extract (HTP-GTE), which has a similar catechin composition to green tea beverages. AIM OF THE STUDY: This study aimed to investigate the effect of HTP-GTE on scopolamine-induced cognitive dysfunction and neuronal differentiation, and to elucidate its underlying mechanisms of action. MATERIALS AND METHODS: The neuronal differentiation promoting effects of HTP-GTE in SH-SY5Y cells was assessed by evaluating neurite length and the expression level of synaptophysin. The DNA methylation status at the synaptophysin promoter was determined in differentiated SH-SY5Y cells and in the hippocampi of mice. HTP-GTE was administered for 10 days at doses of 30, 100 and 300 mg/kg (p.o.) to mice, and its effects on cognitive functions were measured by Y-maze and passive avoidance tests under scopolamine-induced cholinergic blockade state. RESULTS: HTP-GTE induced neuronal differentiation and neurite outgrowth via the upregulation of synaptophysin gene expression. These beneficial effects of HTP-GTE resulted from reducing DNA methylation levels at the synaptophysin promoter via the suppression of DNMT1 activity. The administration of HTP-GTE ameliorated cognitive impairments in a scopolamine-treated mouse model. CONCLUSIONS: These results suggest that HTP-GTE could alleviate cognitive impairment by regulating synaptophysin expression and DNA methylation levels. Taken together, HTP-GTE would be a promising treatment for the cognitive impairment observed in dysfunction of the cholinergic neurotransmitter system.

Casticin ameliorates scopolamine-induced cognitive dysfunction in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Vitex rotundifolia L. (Verbenaceae) has been used in traditional medicine as sedative or analgesic agent for headache. Recent population-based cohort studies have shown that headache including migraines is a risk factor for dementia. Thus, the fruit of V. rotundifolia may be useful for treating cognitive dysfunction observed in dementia. AIM OF THE STUDY: We had previously found that the ethanolic extract of the fruit of V. rotundifolia ameliorated cognitive dysfunction and isolated casticin as an active compound. In the present study, we studied the effect of casticin on a mouse model of cognitive impairment induced by scopolamine. MATERIALS AND METHODS: Mice were treated with the ethanolic extract of the fruit of V. rotundifolia (EEVR; 30, 100 or 300 mg/kg, p.o.) or casticin (0.3, 1 or 3 mg/kg, p.o.). We examined the effect of casticin or EEVR using the passive avoidance test, the Morris water maze test and the novel object recognition test. Scopolamine (1 mg/kg, i.p.) was used to induce cognitive impairment by blocking cholinergic neurotransmitter system. We investigated the effects of casticin on acetylcholinesterase (AchE) activity and the phosphorylation levels of extracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), and the expression levels of brain-derived neurotrophic factor (BDNF). RESULTS: EEVR (100 and 300 mg/kg, p.o.) significantly ameliorated the latency in the passive avoidance test, and casticin (1 and 3 mg/kg, p.o.) also significantly improved the latency in the passive avoidance test, novel object preference in the novel object recognition test, and swimming time in the target quadrant of the Morris water maze test. Casticin also decreased AChE activity in ex vivo analysis and increased the phosphorylation levels of memory-related signaling molecules, such as ERK, CREB and BDNF in the cortex. CONCLUSION: These results suggest that casticin ameliorates cholinergic blockade-induced cognitive impairment, in part, through the inhibition of AChE and the activation of the ERK-CREB-BDNF signaling pathway. Taken together, the results suggest that casticin may be useful for treating the cognitive dysfunction observed during cholinergic impairment.

Multimodal Therapeutic Effects of Neural Precursor Cells Derived from Human-Induced Pluripotent Stem Cells through Episomal Plasmid-Based Reprogramming in a Rodent Model of Ischemic Stroke.

Stem cell therapy is a promising option for treating functional deficits in the stroke-damaged brain. Induced pluripotent stem cells (iPSCs) are attractive sources for cell therapy as they can be efficiently differentiated into neural lineages. Episomal plasmids (EPs) containing reprogramming factors can induce nonviral, integration-free iPSCs. Thus, iPSCs generated by an EP-based reprogramming technique (ep-iPSCs) have an advantage over gene-integrating iPSCs for clinical applications. However, there are few studies regarding the in vivo efficacy of ep-iPSCs. In this study, we investigated the therapeutic potential of intracerebral transplantation of neural precursor cells differentiated from ep-iPSCs (ep-iPSC-NPCs) in a rodent stroke model. The ep-iPSC-NPCs were transplanted intracerebrally in a peri-infarct area in a rodent stroke model. Rats transplanted with fibroblasts and vehicle were used as controls. The ep-iPSC-NPC-transplanted animals exhibited functional improvements in behavioral and electrophysiological tests. A small proportion of ep-iPSC-NPCs were detected up to 12 weeks after transplantation and were differentiated into both neuronal and glial lineages. In addition, transplanted cells promoted endogenous brain repair, presumably via increased subventricular zone neurogenesis, and reduced poststroke inflammation and glial scar formation. Taken together, these results strongly suggest that intracerebral transplantation of ep-iPSC-NPCs is a useful therapeutic option to treat clinical stroke through multimodal therapeutic mechanisms.

Theracurmin Ameliorates Cognitive Dysfunctions in 5XFAD Mice by Improving Synaptic Function and Mitigating Oxidative Stress.

As the elderly population is increasing, Alzheimer's disease (AD) has become a global issue and many clinical trials have been conducted to evaluate treatments for AD. As these clinical trials have been conducted and have failed, the development of new theraphies for AD with fewer adverse effects remains a challenge. In this study, we examined the effects of Theracurmin on cognitive decline using 5XFAD mice, an AD mouse model. Theracurmin is more bioavailable form of curcumin, generated with submicron colloidal dispersion. Mice were treated with Theracurmin (100, 300 and 1,000 mg/kg) for 12 weeks and were subjected to the novel object recognition test and the Barnes maze test. Theracurmin-treated mice showed significant amelioration in recognition and spatial memories compared those of the vehicle-treated controls. In addition, the antioxidant activities of Theracurmin were investigated by measuring the superoxide dismutase (SOD) activity, malondialdehyde (MDA) and glutathione (GSH) levels. The increased MDA level and decreased SOD and GSH levels in the vehicle-treated 5XFAD mice were significantly reversed by the administration of Theracurmin. Moreover, we observed that Theracurmin administration elevated the expression levels of synaptic components, including synaptophysin and post synaptic density protein 95, and decreased the expression levels of ionized calcium-binding adapter molecule 1 (Iba-1), a marker of activated microglia. These results suggest that Theracurmin ameliorates cognitive function by increasing the expression of synaptic components and by preventing neuronal cell damage from oxidative stress or from the activation of microglia. Thus, Theracurmin would be useful for treating the cognitive dysfunctions observed in AD.

Interleukin-1 receptor antagonist-mediated neuroprotection by umbilical cord-derived mesenchymal stromal cells following transplantation into a rodent stroke model.

The human umbilical cord is a promising source of mesenchymal stromal cells (MSCs). Intravenous administration of human umbilical cord-derived MSCs (IV-hUMSCs) showed a favorable effect in a rodent stroke model by a paracrine mechanism. However, its underlying therapeutic mechanisms must be determined for clinical application. We investigated the therapeutic effects and mechanisms of our good manufacturing practice (GMP)-manufactured hUMSCs using various cell doses and delivery time points in a rodent model of stroke. IV-hUMSCs at a dose of 1 × 106 cells at 24 h after stroke improved functional deficits and reduced neuronal damage by attenuation of post-ischemic inflammation. Transcriptome and immunohistochemical analyses showed that interleukin-1 receptor antagonist (IL-1ra) was highly upregulated in ED-1-positive inflammatory cells in rats treated with IV-hUMSCs. Treatment with conditioned medium of hUMSCs increased the expression of IL-1ra in a macrophage cell line via activation of cAMP-response element-binding protein (CREB). These results strongly suggest that the attenuation of neuroinflammation mediated by endogenous IL-1ra is an important therapeutic mechanism of IV-hUMSCs for the treatment of stroke.

Attenuation of Postischemic Genomic Alteration by Mesenchymal Stem Cells: a Microarray Study.

Intravenous administration of mesenchymal stem cells (IV-MSC) protects the ischemic rat brain in a stroke model, but the molecular mechanism underlying its therapeutic effect is unclear. We compared genomic profiles using the mRNA microarray technique in a rodent stroke model. Rats were treated with 1 × 10(6) IV-MSC or saline (sham group) 2 h after transient middle cerebral artery occlusion (MCAo). mRNA microarray was conducted 72 h after MCAo using brain tissue from normal rats (normal group) and the sham and MSC groups. Predicted pathway analysis was performed in differentially expressed genes (DEGs), and functional tests and immunohistochemistry for inflammation-related proteins were performed. We identified 857 DEGs between the sham and normal groups, with the majority of them (88.7%) upregulated in sham group. Predicted pathway analysis revealed that cerebral ischemia activated 10 signaling pathways mainly related to inflammation and cell cycle. IV-MSC attenuated the numbers of dysregulated genes in cerebral ischemia (118 DEGs between the MSC and normal groups). In addition, a total of 218 transcripts were differentially expressed between the MSC and sham groups, and most of them (175/218 DEGs, 80.2%) were downregulated in the MSC group. IV-MSC reduced the number of Iba-1(+) cells in the peri-infarct area, reduced the overall infarct size, and improved functional deficits in MCAo rats. In conclusion, transcriptome analysis revealed that IV-MSC attenuated postischemic genomic alterations in the ischemic brain. Amelioration of dysregulated inflammation- and cell cycle-related gene expression in the host brain is one of the molecular mechanisms of IV-MSC therapy for cerebral ischemia.