Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Effects of osthole on osteoporotic rats: a systematic review and meta-analysis.

CONTEXT: Cnidium monnieri Cusson (Apiaceae) has been used in traditional Asian medicine for thousands of years. Recent studies showed its active compound, osthole, had a good effect on osteoporosis. But there was no comprehensive analysis. OBJECTIVE: This meta-analysis evaluates the effects of osthole on osteoporotic rats and provides a basis for future clinical studies. METHODS: Chinese and English language databases (e.g., PubMed, Web of Science, Cochrane Library, Google Scholar, Embase, China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, Weipu Chinese Sci-tech periodical full-text database, and Chinese BioMedical Literature Database) were searched from their establishment to February 2021. The effects of osthole on bone mineral density, osteoclast proliferation, and bone metabolism markers were compared with the effects of control treatments. RESULTS: To our knowledge, this is the first meta-analysis to evaluate osthole for the treatment of osteoporosis in rats. We included 13 randomized controlled studies conducted on osteoporotic rats. Osthole increased bone mineral density (standardized mean difference [SMD] = 3.08, 95% confidence interval [CI] = 2.08-4.09), the subgroup analysis showed that BMD significantly increased among rats in osthole <10 mg/kg/day and duration of osthole treatment >2 months. Osthole improved histomorphometric parameters and biomechanical parameters, also inhibited osteoclast proliferation and bone metabolism. CONCLUSIONS: Osthole is an effective treatment for osteoporosis. It can promote bone formation and inhibit bone absorption.

Promotion of Bone Formation by Red Yeast Rice in Experimental Animals: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically evaluate the effects of red yeast rice (RYR) and its extract on bone formation in experimental animals and to provide reference data for clinical research on the treatment of osteoporosis. METHODS: Chinese and English language databases, including Web of Science, PubMed, the Cochrane Library, Elsevier, Google Scholar, SpringerLink, Embase, China National Knowledge Infrastructure (CNKI), Weipu Chinese Sci-tech periodical full-text database (VIP), and Wanfang Data Knowledge Service Platform (Wanfang), were searched from their establishment to February 2020 using the following terms: "hongqu," "red yeast rice," "Monascus purpureus-fermented rice," "bone mineral density," "osteoblast," "osteoporosis," and "animal models." After excluding nonrelevant articles, Review Manager 5.2 was used to evaluate article quality and to analyze the data. Outcome indicators included bone mineral density (BMD), osteoblast proliferation, and the expression of alkaline phosphatase (ALP). RESULTS: A total of 11 randomized controlled trials were included in the meta-analysis, all of which were animal studies. Six studies included data on BMD, five on osteoblast proliferation, and six on the expression of ALP. The results of the meta-analysis showed that RYR can significantly improve BMD (standardized mean difference (SMD) = 3.12, 95% confidence interval (CI) 1.41 to 4.83, P = 0.0003), promote osteoblast proliferation (SMD = 1.64, 95% CI 1.04 to 2.23, P < 0.00001), and increase ALP expression in rats (SMD = 1.25, 95% CI 0.69 to 1.80, P < 0.00001). CONCLUSIONS: RYR can promote bone formation in experimental animals and may be useful for the treatment of osteoporosis.

Potential use of SERS-assisted theranostic strategy based on Fe3O4/Au cluster/shell nanocomposites for bio-detection, MRI, and magnetic hyperthermia.

A surface-enhanced Raman scattering (SERS)-assisted theranostic strategy was designed based on a synthesized multifunctional Fe3O4/Au cluster/shell nanocomposite. This theranostic strategy was used for free prostate specific antigen (free-PSA) detection, magnetic resonance imaging (MRI), and magnetic hyperthermia. The lowest protein concentration detected was 1ngmL(-1), and the limit of detection (LOD) of the calculated PSA was 0.75ngmL(-1). Then, MRI was carried out to visualize the tumor cell. Lastly, magnetic hyperthermia was employed and revealed a favorable killing effect for the tumor cells. Thus, this SERS-assisted strategy based on a Fe3O4/Au cluster/shell nanocomposite showed great advantages in theranostic treatment.

GABAergic neurons in cerebellar interposed nucleus modulate cellular and humoral immunity via hypothalamic and sympathetic pathways.

Our previous work has shown that cerebellar interposed nucleus (IN) modulates immune function. Herein, we reveal mechanism underlying the immunomodulation. Treatment of bilateral cerebellar IN of rats with 3-mercaptopropionic acid (3-MP), a glutamic acid decarboxylase antagonist that reduces γ-aminobutyric acid (GABA) synthesis, enhanced cellular and humoral immune responses to bovine serum albumin, whereas injection of vigabatrin, a GABA-transaminase inhibitor that inhibits GABA degradation, in bilateral cerebellar IN attenuated the immune responses. The 3-MP or vigabatrin administrations in the cerebellar IN decreased or increased hypothalamic GABA content and lymphoid tissues' norepinephrine content, respectively, but did not alter adrenocortical or thyroid hormone levels in serum. In addition, a direct GABAergic projection from cerebellar IN to hypothalamus was found. These findings suggest that GABAergic neurons in cerebellar IN regulate immune system via hypothalamic and sympathetic pathways.

Protection of TGF-ß1 against neuroinflammation and neurodegeneration in Aß1-42-induced Alzheimer's disease model rats.

Neuroinflammation has been reported to be associated with Alzheimer's disease (AD) pathogenesis. Neuroinflammation is generally considered as an outcome of glial activation; however, we recently demonstrated that T helper (Th)17 cells, a subpopulation of proinflammatory CD4+ T cells, are also involved in AD pathogenesis. Transforming growth factor (TGF)-ß1, a cytokine that can be expressed in the brain, can be immunosuppressive, but its effects on lymphocyte-mediated neuroinflammation in AD pathogenesis have not been well addressed. In the current study we administered TGF-ß1 via intracerebroventricle (ICV) and intranasal (IN) routes in AD model rats to investigate its antiinflammatory and neuroprotective effects. The AD rat model was prepared by bilateral hippocampal injection of amyloid-ß (Aß)1-42. TGF-ß1 was administered via ICV one hour prior to Aß1-42 injection or via both nares seven days after Aß1-42 injection. ICV administration of TGF-ß1 before Aß1-42 injection remarkably ameliorated Aß1-42-induced neurodegeneration and prevented Aß1-42-induced increases in glia-derived proinflammatory mediators (TNF-α, IL-1ß and iNOS), as well as T cell-derived proinflammatory cytokines (IFN-γ, IL-2, IL-17 and IL-22), in the hypothalamus, serum or cerebrospinal fluid (CSF) in a concentration-dependent manner. TGF-ß1 pretreatment also prevented Aß1-42-induced decreases in the neurotrophic factors, IGF-1, GDNF and BDNF, and in the antiinflammatory cytokine, IL-10. Similarly, IN administration of TGF-ß1 after Aß1-42 injection reduced neurodegeneration, elevation of proinflammatory mediators and cytokines, and reduction of neurotrophic and antiinflammatory factors, in the hypothalamus, serum or CSF. These findings suggest that TGF-ß1 suppresses glial and T cell-mediated neuroinflammation and thereby alleviates AD-related neurodegeneration. The effectiveness of IN administered TGF-ß1 in reducing Aß1-42 neurotoxicity suggests a possible therapeutic approach in patients with AD.

TGF-ß1 protection against Aß1-42-induced neuroinflammation and neurodegeneration in rats.

Transforming growth factor (TGF)-ß1, a cytokine that can be expressed in the brain, is a key regulator of the brain's responses to injury and inflammation. Alzheimer's disease (AD), the most common neurodegenerative disorder, involves inflammatory processes in the brain in addition to the hallmarks, amyloid-ß (Aß) plaques and neurofibrillary tangles. Recently, we have shown that T-helper (Th) 17 cells, a subpopulation of CD4+ T-cells with high proinflammation, also participate in the brain inflammatory process of AD. However, it is poorly known whether TGF-ß1 ameliorates the lymphocyte-mediated neuroinflammation and, thereby, alleviates neurodegeneration in AD. Herein, we administered TGF-ß1 via the intracerebroventricle (ICV) in AD model rats, by Aß1-42 injection in both sides of the hippocampus, to show the neuroprotection of TGF-ß1. The TGF-ß1 administration after the Aß1-42 injection ameliorated cognitive deficit and neuronal loss and apoptosis, reduced amyloid precursor protein (APP) expression, elevated protein phosphatase (PP)2A expression, attenuated glial activation and alleviated the imbalance of the pro-inflammatory/anti-inflammatory responses of T-lymphocytes, compared to the Aß1-42 injection alone. These findings demonstrate that TGF-ß1 provides protection against AD neurodegeneration and suggest that the TGF-ß1 neuroprotection is implemented by the alleviation of glial and T-cell-mediated neuroinflammation.

Cerebellar fastigial nuclear GABAergic projections to the hypothalamus modulate immune function.

Our previous work has shown that the cerebellar fastigial nucleus (FN) is involved in modulation of lymphocyte function. Herein, we investigated effect of FN γ-aminobutyric acid (GABA)-ergic projections to the hypothalamus on lymphocytes to understand pathways and mechanisms underlying cerebellar immunomodulation. By injection of Texas red dextran amine (TRDA), an anterograde tracer, into FN, we found that the TRDA-labeled fibers from the FN traveled through the superior cerebellar peduncle (SCP), crossed in decussation of SCP (XSCP), entered the hypothalamus, and primarily terminated in the lateral hypothalamic area (LHA). Further, by injecting Fluoro-Ruby (FR), a retrograde tracer, in LHA, we observed that the FR-stained fibers retrogradely passed through XSCP and reached FN. Among these FR-positive neurons in the FN, there were GABA-immunoreactive cells. We then microinjected vigabatrin, which is an inhibitor of GABA-transaminase (GABA-T) that degrades GABA, bilaterally into FN. The vigabatrin treatment increased both number of GABA-immunoreactive neurons in FN-LHA projections and GABA content in the hypothalamus. Simultaneously, vigabatrin significantly reduced concanavalin A (Con A)-induced lymphocyte proliferation, anti-sheep red blood cell (SRBC) IgM antibody level, and natural killer (NK) cell number and cytotoxicity. In support of these findings, we inhibited GABA synthesis by using 3-mercaptopropionic acid (3-MP), which antagonizes glutamic acid decarboxylase (GAD). We found that the inhibition of GABA synthesis caused changes that were opposite to those when GABA was increased with vigabatrin. These findings show that the cerebellar FN has a direct GABAergic projection to the hypothalamus and that this projection actively participates in modulation of lymphocytes.

Effect of Cerebellohypothalamic Glutamatergic Projections on Immune Function.

Our previous work has shown that lesions of the cerebellar interposed nuclei (IN) suppress immune cell functions. Since there is no direct structural connection between the cerebellum and immune system, we explored the pathway mediating the cerebellar immunomodulation at the profile of cerebellohypothalamic projections to understand this modulation. Anterograde tracing of nerve tracts from the cerebellar IN to the hypothalamus was conducted by injection of anterograde tracer dextran-texas red (dextran-TR) in the cerebellar IN. We observed that dextran-TR-labeled nerve fibers, which were sent by cerebellar IN neurons, traveled in the superior cerebellar peduncle (SCP), crossed in SCP decussation, and entered the hypothalamus. In the hypothalamus, the fibers mostly terminated in the lateral hypothalamic area (LHA). Retrograde tracing by injection of retrograde tracer fluoro-ruby (FR) in the LHA found that FR-labeled neurons appeared in contralateral cerebellar IN. Fluorescent immunohistochemistry for glutamate revealed that many of the FR-labeled neurons were glutamatergic. These results demonstrate a direct glutamatergic projection from the cerebellar IN to the LHA. Reduction of the cerebellohypothalamic glutamatergic projections by microinjection of 6-diazo-5-oxo- L-norleucine (DON), an inhibitor of glutaminase for glutamate synthesis, in bilateral cerebellar IN led to suppression of peripheral lymphocyte number, T lymphocyte proliferation, and serum anti-sheep red blood cell IgM level. But the DON injection in the cerebellar cortex that does not send axons to the hypothalamus did not significantly alter all the immune parameters. These findings suggest that cerebellohypothalamic glutamatergic projection modulates immune function, and that via the pathway, the cerebellum implements its immunoregulatory effect.

Clinical observation on acupuncture treatment of intractable insomnia.

OBJECTIVE: To observe the effects of acupuncture for treatment of intractable insomnia. METHODS: Totally 90 patients were randomly divided into a treatment group (50 cases), treated by the body acupuncture plus auricular-plaster therapy, and a control group (40 cases), the Baihui (GV 20)-through-Sishencong (EX-HN1). puncture, auricular-plaster therapy and moxibustion on the back-shu points were not used in the control group. The clinical effects were observed. RESULTS: The total effective rate was 98.0% in the treatment group and 77.5% in the control group. The therapeutic effect in the treatment group was much better than that in the control group (P < 0.01). CONCLUSION: The body acupuncture plus auricular-plaster therapy may show better effect for intractable insomnia.