Search

Lumbar facet joints have been implicated in chronic low back pain in up to 45% of patients with low back pain (LBP). Facet joint pain diagnosis and management are always challenging for pain physicians. Facet joint pain is not diagnosed by specific demographic features, pain characteristics, or physical findings, even though electrodiagnostic studies and imaging modalities are available. Although comparative local anesthetics or placebo saline injections can be used, diagnostic blocks are the only reliable diagnostic measures according to the current literature. Treatment of chronic LBP arising due to facet joint includes intraarticular injections, medial branch blocks, and radiofrequency neurotomy. However, the evidence of their clinical efficacy is continuously under scrutiny. Pain physicians must have a detailed understanding of the spinal anatomy in order to perform safe and effective interventional procedures. This review outlines the important aspects of spinal anatomy as they relate to interventional pain management related to facet joint injections. Additionally, we provide a comprehensive review of the procedure and clinical evidence.

Background The aim of this study was to clarify the topographical relationship between the accessory nerve (AN) and transverse cervical artery (TCA) to provide safe and convenient injection points for AN blockade. Methods This study included 21 and 30 shoulders of 14 embalmed Korean adult cadavers and 15 patients, respectively, for dissection and ultrasound (US) examination. Results The courses of the TCA and AN in the scapular region were classified into four types based on their positional relationships. Type A indicated the nerve that was medial to the artery and ran parallel without changing its location (38%). In type B (38%), the nerve was lateral to the artery and ran parallel without changing its location. In type C (19%), the nerve or artery traversed each other only once during the whole course. In type D (5%), the nerve or artery traversed each other more than twice forming a twist. At the levels of lines I-IV, the nerve was relatively close to the artery (approximately 10 mm). TCAs were observed in all specimens around the superior angle of the scapula at the level of line II, whereas they were not found below line VI. In US images of the patients, the TCA was commonly observed at the level of line II (93.3%) where all ANs and TCAs were observed in cadaveric dissection. Conclusions The results expand the current knowledge of the relation between the AN and TCA, and provide helpful information for selective diagnostic nerve blocks in the scapular region.

Among the animal models of Parkinson’s disease (PD), the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model has shown both dopaminergic (DA) damage and related motor control defects, as observed in patients with PD. Recent studies have suggested that the DA system interacts with the synaptic plasticity of the hippocampus in PD. However, little is known about how alterations in the hippocampal structural plasticity are affected by the DA damage in MPTP-lesioned models. In the present study, we investigated alterations in dendritic complexity and spine density in the mouse hippocampus following acute MPTP treatment (22 mg/kg, intraperitoneally, four times/day, 2-h intervals). We confirmed that acute MPTP treatment significantly decreased initial motor function and persistently reduced the number of tyrosine hydroxylase-positive DA neurons in the substantia nigra. Golgi staining showed that acute MPTP treatment significantly reduced the spine density of neuronal dendrites in the cornu ammonis 1 (CA1) apical/basal and dentate gyrus (DG) subregions of the mouse hippocampus at 8 and 16 days after treatment, although it did not affect dendritic complexity (e.g., number of crossing dendrites, total dendritic length, and branch points per neuron) in both CA1 and DG subregions at all time points after treatment. Therefore, the present study provides anatomical evidence that acute MPTP treatment affects synaptic structure in the hippocampus during the late phase after acute MPTP treatment in mice, independent of any changes in the dendritic arborization of hippocampal neurons. These findings offer data for the ability of the acute MPTP-lesioned mouse model to replicate the non-nigrostriatal lesions of clinical PD.

Background: The aim of this study was to clarify the topographical relationships between the dorsal scapular nerve (DSN) and the dorsal scapular artery (DSA) in the interscapular region to identify safe and convenient injection points related to DSN blockade. Methods: Thirty shoulders of embalmed Korean cadavers and 50 live subjects were used for dissection and ultrasound (US) analysis. Results: The running patterns of the DSA and DSN in the interscapular region were classified into 3 types. Type I was defined as nerves that were medial to the artery and parallel without changing location (80.0% of specimens). In type II (13.3%), the nerve and artery traversed one another only one time over their entire length. In type III (6.7%), the nerve and artery traversed one another, resembling a twist. Above the level of the scapular spine, the nerve was always medial to the artery. Below the scapular spine, the number of arteries was obviously decreased. Most of the arteries were lateral to the medial border of the scapula, except at the level of the superior angle of the scapula artery (SA). The positional tendency of the DSN toward the medial or lateral sides from the medial border of the scapula was similar. In US imaging of live subjects, the DSA was most observed at the level of the SA (94.0%). Conclusions: Results of this study enhance the current knowledge regarding the pathway of the DSN and DSA and provide helpful information for selective diagnostic nerve blocks in the interscapular region.

Chemotherapeutic agents induce long-term side effects, including cognitive impairment and mood disorders, particularly in breast cancer survivors who have undergone chemotherapy. However, the precise mechanisms underpinning chemotherapy-induced hippocampal dysfunction remain unknown. In this study, we investigated the detrimental effects of chronic treatment with a combination of adriamycin and cyclophosphamide (AC) on the neuronal architecture and functions of the hippocampi of female C57BL/6 mice. After chronic AC administration, mice showed memory impairment (measured using a novel object recognition memory task) and depression-like behavior (measured using the tail suspension test and forced swim test). According to Golgi staining, chronic AC treatment significantly reduced the total dendritic length, ramification, and complexity as well as spine density and maturation in hippocampal neurons in a sub-region-specific manner. Additionally, the AC combination significantly reduced adult neurogenesis, the extent of the vascular network, and the levels of hippocampal angiogenesis-related factors. However, chronic AC treatment did not increase the levels of inflammation-related signals (microglial or astrocytic distribution, or the levels of pro-inflammatory cytokines or M1/M2 macrophage markers). Thus, chronic AC treatment changed the neuronal architecture of the adult hippocampus, possibly by reducing neurogenesis and the extent of the vasculature, independently of neuroinflammation. Such detrimental changes in micromorphometric parameters may explain the hippocampal dysfunction observed after cancer chemotherapy., Graphical Abstract

Brain exposure to ionizing radiation can cause functional deficits in the hippocampus, including memory impairment. However, the specific molecular mechanisms underlying irradiation-induced cognitive impairments are largely unknown. Changes in DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), which are involved in DNA methylation and histone remodeling, may be associated with behavioral changes in learning and memory. We assessed changes in the levels of enzymes associated with the epigenetic modification of gene expression, including DNMT1, HDAC1, HDAC2, Sirtuin 1 (SIRT1), and acetylated histone H3 (Ace-H3) in the mouse hippocampus 1 and 30days after a single exposure to cranial irradiation (0 or 10Gy). mRNA levels of HDAC1 were significantly downregulated 1day after irradiation with 10Gy, and those of DNMT1, HDAC1, and HDAC2 were significantly downregulated 30days post-irradiation. Western blot analysis revealed significant decreases in DNMT1, HDAC1, and HDAC2 protein levels 1 and 30days after irradiation with 10Gy. Furthermore, protein levels of SIRT1 and Ace-H3 were significantly downregulated in the mouse hippocampus 1 and 30days after cranial irradiation. Our findings suggest that the reduction in epigenetic gene expression is associated with hippocampal dysfunction in mice exposed to cranial irradiation.

The aim of this study was to clarify the distribution patterns of the cutaneous nerves on the dorsum of the foot. This study investigated 130 feet of 77 cadavers. The distribution patterns of the sural (SN) and deep fibular nerves (DFN) were classified into five and four types, respectively. In Type A, the SN was only distributed to the lateral side of the fifth toe. In Type B, the nerve was distributed to the medial side of the fourth toe and both sides of the fifth toe. In Type C, the nerve was mainly distributed to the lateral side of the fifth toe. In Type D, the nerve was distributed to the lateral side of the third toe and both sides of the fourth and fifth toes. In Type E, no SN was found. In Type α, the DFN was simultaneously distributed to the lateral side of the first toe and the medial side of the second toe. In Type β, the nerve was distributed like in Type α and additionally to the medial side of the first toe. In Type γ, the nerve was distributed like in Type α and additionally to the lateral side of the second toe and the medial side of the third toe. In Type δ, no DFN was found. The results of this study will help physicians to reduce the incidence of iatrogenic nerve injury and improve the quality of diagnoses of relevant nerves in this body region. Clin. Anat. 33:592-597, 2020. © 2019 Wiley Periodicals, Inc.

Cranial irradiation can trigger adverse effects on brain functions, including cognitive ability. However, the cellular and molecular mechanisms underlying radiation-induced cognitive impairments remain still unknown. Immediate-early genes (IEGs) are implicated in neuronal plasticity and the related functions (i.e., memory formation) in the hippocampus. The present study quantitatively assessed changes in the mRNA and protein levels of the learning-induced IEGs, including Arc, c-fos, and zif268, in the mouse hippocampus after cranial irradiation using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively. Mice (male, 8-week-old C57BL/6) received whole-brain irradiation with 0 or 10Gy of gamma-ray and, 2weeks later, contextual fear conditioning (CFC) was used to induce IEGs. In the CFC task, mice evaluated 2weeks after irradiation exhibited significant memory deficits compared with sham (0Gy)-irradiated controls. The levels of mRNA encoding IEGs were significantly upregulated in the hippocampus 10 and 30min after CFC training. The mRNA levels in the irradiated hippocampi were significantly lower than those in the sham-irradiated controls. The IEG protein levels were significantly increased in all hippocampal regions, including the hippocampal dentate gyrus, cornu ammonis (CA)1, and CA3, after CFC training. The CFC-induced upregulation of Arc and c-fos in 10Gy-irradiated hippocampi was significantly lower than that in sham-irradiated controls, although there were no significant differences in the protein levels of the learning-induced zif268 between sham-irradiated and 10Gy-irradiated hippocampi. Thus, cranial irradiation with 10Gy of gamma-ray impairs the induction of hippocampal IEGs (particularly Arc and c-fos) via behavioral contextual fear memory, and this disturbance may be associated with the memory deficits evident in mice after cranial irradiation, possibly through the dysregulation of neuronal plasticity during memory formation.

Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term potentiation (LTP) and memory formation in mice lacking type 1 adenylyl cyclase (AC1), a neurospecific synaptic enzyme that contributes to Ca2+-stimulated cAMP production. Following 1 mo of voluntary running-wheel exercise, the impaired LTP and object recognition memory in AC1 knockout (KO) mice were significantly attenuated. Running up-regulated exon II mRNA level of BDNF (brain-derived neurotrophic factor), though it failed to increase exon I and IV mRNAs in the hippocampus of AC1 KO mice. Intrahippocampal infusion of recombinant BDNF was sufficient to rescue LTP and object recognition memory defects in AC1 KO mice. Therefore, voluntary running and exogenous BDNF application overcome the defective Ca2+-stimulated cAMP signaling. Our results also demonstrate that alteration in Ca2+-stimulated cAMP can affect the molecular outcome of physical exercise.

The hippocampus (HPC) is known to play an important role in learning, a process dependent on synaptic plasticity; however, the molecular mechanisms underlying this are poorly understood. ΔFosB is a transcription factor that is induced throughout the brain by chronic exposure to drugs, stress, and variety of other stimuli and regulates synaptic plasticity and behavior in other brain regions, including the nucleus accumbens. We show here that ΔFosB is also induced in HPC CA1 and DG subfields by spatial learning and novel environmental exposure. The goal of the current study was to examine the role of ΔFosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence ΔFosB transcriptional activity by expressing ΔJunD (a negative modulator of ΔFosB transcriptional function) or to overexpress ΔFosB, we demonstrate that HPC ΔFosB regulates learning and memory. Specifically, ΔJunD expression in HPC impaired learning and memory on a battery of hippocampal-dependent tasks in mice. Similarly, general ΔFosB overexpression also impaired learning. ΔJunD expression in HPC did not affect anxiety or natural reward, but ΔFosB overexpression induced anxiogenic behaviors, suggesting that ΔFosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of ΔFosB increases immature dendritic spines on CA1 pyramidal cells, whereas ΔJunD reduced the number of immature and mature spine types, indicating that ΔFosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that ΔFosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory.SIGNIFICANCE STATEMENTConsolidation of our explicit memories occurs within the hippocampus, and it is in this brain region that the molecular and cellular processes of learning have been most closely studied. We know that connections between hippocampal neurons are formed, eliminated, enhanced, and weakened during learning, and we know that some stages of this process involve alterations in the transcription of specific genes. However, the specific transcription factors involved in this process are not fully understood. Here, we demonstrate that the transcription factor ΔFosB is induced in the hippocampus by learning, regulates the shape of hippocampal synapses, and is required for memory formation, opening up a host of new possibilities for hippocampal transcriptional regulation.

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter involved in synaptic plasticity. GABAergic transmission is also implicated in developmental and degenerative processes in the brain. The goal of the present study was to understand the developmental and degenerative regulation of GABAergic transmission in the mouse hippocampus by examining changes in GABA receptor subunit mRNA levels and GABA-related protein expression during postnatal development of the hippocampus and trimethyltin (TMT)-induced neurodegeneration in the juvenile (postnatal day [PD] 24) and adult hippocampus (PD 56). During postnatal development, the mRNA levels of GABA A receptor (GABAAR) subunits, including α1, α4, β1, β2, and δ; GABA B receptor (GABABR) subunit 2; and the expression of GABA-related proteins, including glutamic acid decarboxylase, vesicular GABA transporter (VGAT), and potassium chloride cotransporter 2 increased gradually in the mouse hippocampus. The results of seizure scoring and histopathological findings in the hippocampus revealed a more pronounced response to the same administered TMT dose in juvenile mice, compared with that in adult mice. The mRNA levels of most GABA receptor subunits in the juvenile hippocampus, excluding GABAAR subunit β3, were dynamically altered after TMT treatment. The mRNA levels of GABAAR subunits γ2 and δ decreased significantly in the adult hippocampus following TMT treatment, whereas the level of GABABR subunit 1 mRNA increased significantly. Among the GABA-related proteins, only VGAT decreased significantly in the juvenile and adult mouse hippocampus after TMT treatment. In conclusion, regulation of GABAergic signaling in the mouse hippocampus may be related to maturation of the central nervous system and the degree of neurodegeneration during postnatal development and TMT-induced neurodegeneration in the experimental animals.

Cranial irradiation (IR) is commonly used for the treatment of brain tumors but may cause disastrous brain injury, especially in the hippocampus, which has important cognition and emotional regulation functions. Several preclinical studies have investigated the mechanisms associated with cranial IR-induced hippocampal dysfunction such as memory defects and depression-like behavior. However, current research on hippocampal dysfunction and its associated mechanisms, with the ultimate goal of overcoming the side effects of cranial radiation therapy in the hippocampus, is still very much in progress. This article reviews several in vivo studies on the possible mechanisms of radiation-induced hippocampal dysfunction, which may be associated with hippocampal neurogenesis, neurotrophin and neuroinflammation. Thus, this review may be helpful to gain new mechanistic insights into hippocampal dysfunction following cranial IR and provide effective strategies for potential therapeutic approaches for cancer patients receiving radiation therapy.

Nestin is a protein of embryonic intermediate filaments expressed by multipotent neural stem cells. In the present study, the nestin expression pattern in the mouse hippocampus 1, 2, 3, 4, and 8 days after treatment with trimethyltin (TMT) was examined to explore the possible role played by nestin in chemically induced hippocampal injury. TMT treatment (2.5mg/kg, intraperitoneally) selectively injured the dentate gyrus (DG) of the mouse hippocampus. The level of hippocampal mRNA encoding nestin increased significantly 2 and 3 days post-treatment and thereafter decreased (at 4 and 8 days post-treatment). The level of nestin protein significantly increased 2 - 4 days post-treatment, particularly in the injured region of the DG, and predominantly in glial fibrillary acidic protein-positive astrocytes in the hippocampal DG. Ki67-positive proliferating cells were increased following TMT treatment and co-localized with nestin-positive reactive astrocytes. Thus, we suggest that nestin contributes to remodeling of the chemically injured DG via glial scar formation and the alteration of neurogenesis.

Panax ginseng, also known as Korean ginseng, has long been used as a broad tonic in Oriental medicine to augment vitality, health, and longevity, particularly in older people. This study investigated the effects of Korean red ginseng (RG) on bone loss in ovariectomized (OVX) mice. C3H/HeN mice (10-weeks-old) were divided into sham and OVX groups. OVX mice were treated with vehicle, 17β-estradiol (E₂), RG (oral administration, 250 mg/kg/day), or RG (intraperitoneal administration, 50 mg/kg/every other day) for 6 weeks. Serum E₂ concentration and alkaline phosphatase (ALP) activity were measured. Tibiae were analyzed using microcomputed tomography. Biomechanical properties and osteoclast surface level were measured. There was no significant difference in the degree of grip strength, body weight, uterine weight, mechanical property, tibiae length, or tibiae weight between the OVX and RG-treated groups. Compared with the OVX group, the serum ALP level was significantly lower in the RG-treated groups. Serum E₂ levels and osteoclast surface levels did not change between the OVX and RG-treated groups. RG could not preserve trabecular bone volume, trabecular bone number, trabecular separation, trabecular thickness, structure model index, or bone mineral density of the proximal tibiae metaphysic. In conclusion, there was no definite effect of RG on OVX-induced bone loss in C3H/HeN mice.

Individuals with cancer are particularly susceptible to depression and cognitive impairment. However, the precise mechanisms underlying cancer-induced hippocampal dysfunction are poorly understood. We investigated the effects of a peripheral tumor on emotional behavior, hippocampus-dependent memory and associated molecular and cellular features using an experimental animal model. Behavioral alterations were examined; stress-related parameters measured; hippocampal neurogenesis evaluated; and the levels of pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (COX-2) assayed, 2 weeks after inoculation of adult BALB/c mice with cells of a colon carcinoma cell line (CT26). As the tumors developed, CT26-inoculated mice showed significant increases in the depression-like behavior (measured using the tail suspension test) and memory impairment (in terms of object recognition) compared with vehicle-inoculated controls. The presence of a peripheral tumor significantly elevated the hippocampal levels of mRNAs encoding interleukin-6 (IL-6) and tumor necrosis factor-α, as well as plasma IL-6 and corticosterone levels. Additionally, the adrenal glands became enlarged, and the numbers of Ki-67-positive proliferating hippocampal cells and doublecortin-positive immature progenitor neurons, as well as the constitutive levels of mRNAs encoding BDNF and COX-2 were significantly reduced. Therefore, a peripheral tumor alone may be sufficient to induce hippocampal dysfunction, possibly by reducing the rate of neurogenesis and the levels of BDNF and COX-2 in that tissue and also by increasing stress-related parameters and the circulating levels of pro-inflammatory cytokines.

Sodium butyrate is a histone deacetylase inhibitor that affects various types of brain damages. To investigate the effects of sodium butyrate on hippocampal dysfunction that occurs after whole-brain irradiation in animal models and the effect of sodium butyrate on radiation exposure-induced cognitive impairments, adult C57BL/6 mice were intraperitoneally treated with 0.6 g/kg sodium butyrate before exposure to 10 Gy cranial irradiation. Cognitive impairment in adult C57BL/6 mice was evaluated via an object recognition test 30 days after irradiation. We also detected the expression levels of neurogenic cell markers (doublecortin) and phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor. Radiation-exposed mice had decreased cognitive function and hippocampal doublecortin and phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor expression. Sodium butyrate pretreatment reversed these changes. These findings suggest that sodium butyrate can improve radiation-induced cognitive dysfunction through inhibiting the decrease in hippocampal phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor expression. The study procedures were approved by the Institutional Animal Care and Use Committee of Korea Institute of Radiological Medical Sciences (approval No. KIRAMS16-0002) on December 30, 2016.

This study investigated the effects of Korean Red Ginseng (KRG) on radiation-induced bone loss in C3H/HeN mice. C3H/HeN mice were divided into sham and irradiation (3 Gy, gamma-ray) groups. The irradiated mice were treated for 12 wk with vehicle, KRG (per os, p.o.) or KRG (intraperitoneal). Serum alkaline phosphatase (ALP), tartrate-resistant acid phosphatase, estradiol level, and biomechanical properties were measured. Tibiae were analyzed using micro-computed tomography. Treatment of KRG (p.o., 250 mg/kg of body weight/d) significantly preserved trabecular bone volume, trabecular number, structure model index, and bone mineral density of proximal tibia metaphysic, but did not alter the uterus weight of the mice. Serum ALP level was slightly reduced by KRG treatment. However, grip strength, mechanical property, and cortical bone architecture did not differ among the experimental groups. The results indicate that KRG can prevent radiation-induced bone loss in mice.

Aim To examine whether a hospitalist-directed interdisciplinary (ITD) team in an internal medicine residency program enhances the hospital and clinical outcomes for seniors with acute medical illness. Methods Seniors admitted to a USA teaching hospital medical floor-teaching services were allocated to the ITD (n = 379) and usual care teams (n = 383). Compared with the usual care team, the ITD team physicians carried out daily “geriatric” assessment and management, and led ITD team meetings. Results The mean probability of functional decline on hospital discharge in the ITD team (25%; 95% CI 19–30%) was significantly lower than that in the usual care team (36%; 95% CI 30–43%; OR 0.35; 95% CI 0.10–0.92; P

To evaluate the acute to chronic effects of crude oil exposure on hematological and blood biochemical toxicities, Sprague-Dawley rats were given by oral doses of 0, 50 or 100 mg/kg BW/day of Iranian heavy crude oils for four weeks. In the acute phase of exposure (1 day after 4 weeks oil treatment), decreases in weight of thymus, serum level of interferon gamma (IFN-γ), superoxide dismutase (SOD) and catalase activities in liver or kidney, and increase in weight of adrenal gland occurred after oral administration of crude oil. In body weight, histopathological examination, hematological and blood biochemical analyses in the acute phase of exposure, there were no significant differences among the experimental groups. In the subchronic and chronic phase of exposure (2 months and 6 months after 4 weeks oil treatment), the changes of biomarkers were normalized except the indicators of oxidative stress. Our findings show that the bioassay on the indicators of oxidative stress is a sensitive method for determining exposure to crude oil in rat.

Trimethyltin (TMT) is an organotin neurotoxicant with effects that are selectively localized to the limbic system (especially the hippocampus), which produces memory deficits and temporal lobe seizures. Galectin-3 (Gal-3) is a beta-galactoside-binding lectin that is important in cell proliferation and regulation of apoptosis. The present study evaluated the temporal expression of Gal-3 in the hippocampus of adult BALB/c mice after TMT treatment (i.p., 2.5mg/kg). Western blotting analyses showed that Gal-3 immunoreactivity began to increase days after treatment; the immunoreactivity peaked significantly within days after treatment but significantly declined between days 4 and 8. Immunohistochemical analysis indicated that Gal-3 expression was very rare in the hippocampi of vehicle-treated controls. However, Gal-3 immunoreactivity appeared between 2 and 8 days after TMT treatment and was primarily localized to the hippocampal dentate gyrus (DG), in which neuronal degeneration occurred. The immunoreactivity was detected predominantly in most of the Iba1-positive microglia and in some GFAP-positive astrocytes of the hippocampal DG. Furthermore, Gal-3 expression co-localized with the pro-inflammatory enzymes cyclooxygenase-2 and inducible nitric oxide synthase in the hippocampal DG. Therefore, we suggest that Gal-3 is involved in the inflammatory process of neurodegenerative disorder induced by organotin intoxication.

Trimethyltin (TMT), a toxic organotin compound, induces neurodegeneration selectively involving the limbic system and especially prominent in the hippocampus. Neurodegeneration-associated behavioral abnormalities, such as hyperactivity, aggression, cognitive deficits, and epileptic seizures, occur in both exposed humans and experimental animal models. Previously, TMT had been used generally in industry and agriculture, but the use of TMT has been limited because of its dangers to people. TMT has also been used to make a promising in vivo rodent model of neurodegeneration because of its region-specific characteristics. Several studies have demonstrated that TMT-treated animal models of epileptic seizures can be used as tools for researching hippocampus-specific neurotoxicity as well as the molecular mechanisms leading to hippocampal neurodegeneration. This review summarizes the in vivo and in vitro underlying mechanisms of TMT-induced hippocampal neurodegeneration (oxidative stress, inflammatory responses, and neuronal death/survival). Thus, the present review may be helpful to provide general insights into TMT-induced neurodegeneration and approaches to therapeutic interventions for neurodegenerative diseases, including temporal lobe epilepsy.

Background Excessive osteoclast activity is a major cause of metabolic bone disorders, such as osteopenia, rheumatoid arthritis, and osteoporosis. Thus, discovery of agents targeting osteoclast differentiation and bone resorption is important for development of novel treatments for bone diseases. It has been demonstrated that ethanolic extract of schizonepeta tenuifolia (EEST) has potent anti-oxidant and anti-inflammatory activities. However, the beneficial effects of EEST on bone metabolism have not been studied. Therefore, we intend to investigate the effects of EEST on osteoclast differentiation. Methods We examined the effects and mechanisms of action of the EEST on osteoclastogenesis in vitro in bone marrow macrophages (BMMs) stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL) and in vivo using a mouse model of lipopolysaccharide (LPS)-induced bone destruction. Results We found that EEST inhibited phosphorylation of Akt and IkB at early stages of RANKL-induced osteoclastogenesis. Furthermore, EEST negatively controlled the transcription and translation levels of nuclear factor of activated T cells c1 (NFATc1) and the translation level of c-Fos at the final stage of osteoclast differentiation. Reflecting these effects, EEST blocked both filamentous actin (F-actin) ring formation and bone resorbing activity of mature osteoclasts in vitro. The inhibitory effects of EEST on osteoclast formation and activity were observed in an LPS-mediated bone erosion mouse model using micro-CT and histological analysis. Conclusions EEST is a potential agent that is able to treat osteoclast-related bone diseases, such as osteoporosis.

Dendrobium moniliforme (DM) is a well-known plant-derived extract that is widely used in Oriental medicine. DM and its chemical constituents have been reported to have a variety of pharmacological effects, including anti-oxidative, anti-inflammatory, and anti-tumor activities; however, no reports discuss the beneficial effects of DM on bone diseases such as osteoporosis. Thus, we investigated the relationship between DM and osteoclasts, cells that function in bone resorption. We found that DM significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation; DM directly induced the down-regulation of c-Fos and nuclear factor of activated T cells c1 (NFATc1) without affecting other RANKL-dependent transduction pathways. In the later stages of osteoclast maturation, DM negatively regulated the organization of filamentous actin (F-actin), resulting in impaired bone-resorbing activity by the mature osteoclasts. In addition, micro-computed tomography (μ-CT) analysis of the murine model revealed that DM had a beneficial effect on lipopolysaccharide (LPS)-mediated bone erosion. Histological analysis showed that DM attenuated the degradation of trabecular bone matrix and formation of TRAP-positive osteoclasts in bone tissues. These results suggest that DM is a potential candidate for the treatment of metabolic bone disorders such as osteoporosis.

Methotrexate (MTX) is a well-known cytostatic agent used in adjuvant chemotherapy for breast cancer, that has neurological side effects, including depression and cognitive impairment. We investigated the neurotoxic effects of MTX on the hippocampus and hippocampus-dependent behaviors in breast cancer cell line (FM3A)-inoculated tumor-bearing mice. In addition, we evaluated the changes in inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the hippocampus of tumor-bearing mice after treatment with MTX. Depressive-like behavior test (tail-suspension test, TST) and learning and memory tasks (passive avoidance) were administered 24 h after MTX (40 mg/kg, i.p.) injection. MTX-treated tumor-bearing mice showed significant depressive-like behaviors and cognitive impairment. Treatment with MTX significantly decreased the number of doublecortin (a marker for immature progenitor neurons)-positive cells in the hippocampal dentate gyrus of tumor-free and tumor-bearing mice. Moreover, treatment with MTX significantly upregulated proinflammatory enzymes, including iNOS and COX-2, in tumor-bearing mice. These findings indicate that the acute neurotoxic effect of MTX leads to hippocampal dysfunction including depressive-like behaviors and memory deficits, which may be related to an inhibition of neurogenesis and an increase of the inflammatory response in the hippocampus of a mouse model of breast cancer.

Received January 5, 2012 /Revised April 12, 2012 /Accepted May 8, 2012 The present study evaluated the localization of luteinizing hormone receptors (LHR) and galectin-3 (Gal-3), a beta-galactoside-binding animal lectin, in the mature mouse ovaries by immunohistochemical analysis. Intense LHR immunoreactivity was detected in the active corpus luteum (CL), whereas expression of Gal-3 was high in the regressing CL and atretic follicle. In the CL of pregnant mice, LHR immunoreactivity was intense, but Gal-3 expression was low. Thus, LHR and Gal-3 had opposite patterns of expression in mature mouse ovaries, suggesting that both proteins have stage-specific expression patterns and are possibly involved in CL formation and regression.

Cimicifugae rhizoma might be protective against osteoporosis. This study investigated the effects of Cimicifuga heracleifolia (CH), an Asian species of Cimicifugae rhizome, on bone loss in ovariectomized (OVX) mice. The C3H/HeN mice were divided into sham and OVX groups. The OVX mice were treated with vehicle, 17β-estradiol (E2) or CH for 6 weeks. Serum calcium, phosphorus, E2 concentration and serum alkaline phosphatase (ALP) activity were measured. Tibiae and femora were analysed using microcomputed tomography. The biomechanical property and osteoclast surface level were measured. Treatment with CH (i.p., 50 mg/kg of body weight, every other day) prevented the OVX-induced increase in body weight but did not alter the uterus weight of the OVX mice. Serum ALP levels and osteoclast surface levels in the OVX mice were reduced by treatment with CH. The CH significantly preserved trabecular bone mass, bone volume, trabecular number, trabecular thickness, structure model index and bone mineral density of proximal tibia metaphysis or distal femur metaphysis. However, grip strength, mechanical property and cortical bone architecture did not differ among the experimental groups. The results indicate that the supply of CH can prevent OVX-induced bone loss in mice. Copyright © 2011 John Wiley & Sons, Ltd.

This study investigated whether methotrexate (MTX) is neurotoxic to neural progenitor cells in the hippocampus of adult mice and whether it affects hippocampus-dependent behaviors. In addition, the cytotoxicity of MTX was elucidated in rat immature and mature hippocampal cultured cells. The number of Ki-67 (proliferating cell marker)- and doublecortin (immature progenitor neuron marker)-positive cells were significantly time- and dose-dependently changed in the dentate gyrus of adult hippocampi after MTX treatment. A learning and memory task (object recognition memory test) and depression-like behavior test (tail-suspension test) were performed after MTX treatment to assess hippocampal neurogenesis-related behavioral dysfunction. MTX-treated mice showed significant depression-like behaviors and memory defects. The cytotoxicity of MTX in immature hippocampal cells varied in a dose-dependent pattern, but was not changed in the mature cells. MTX induced marked apoptotic changes in immature hippocampal cells, with increase in active caspase-3 and cleaved poly (ADP-ribose) polymerase expressions. Results of this study suggest that the neurotoxic effect of MTX inhibits the proliferation of hippocampal progenitor cells and can cause hippocampal dysfunction, such as depression and cognitive impairment. Additionally, the significantly greater caspase-dependent MTX sensitivity of immature hippocampal cells suggests that the susceptibility of such hippocampal cells depends on their maturation.

It has been clinically reported that toluene causes mental depression in humans. However, the detrimental effects of toluene exposure on brain function and the relation between features of mental depression and toluene exposure are poorly understood. This study evaluated depression-like behaviors in adult C57BL/6 mice after administration of toluene, and elucidated the effects of classical antidepressants on the depression-like behaviors. For the estimation of depression-like behaviors, tail suspension test (TST) and forcedswim test (FST) were performed 1, 4 and 16 days after toluene (0~1000 mg/kg bw) treatment. In addition, classical antidepressants such as fluoxetine (FLX, 20 mg/kg bw) and imipramine (IMI, 40 mg/kg bw) were administered 12 h and 1 h before the tests. In the TST and FST, toluene-treated mice exhibited a longer duration of immobility than vehicle-treated mice 1 and 4 days after toluene treatment. The depression-like behaviors were significantly reversed by FLX and IMI. The weight of the adrenal gland and the size of adrenocortical cells were significantly higher in toluene-treated mice compared to vehicle-treated controls. It is suggested that acute toluene exposure of adult mice is sufficiently detrimental to induce depression. In addition, this study has established a mouse model for a depressive state induced by toluene treatment.

This study was performed to examine whether elevated activity of cAMP responsive element-binding protein (CREB) attenuates the detrimental effects of acute gamma (γ) -irradiation on hippocampal neurogenesis and related functions. C57BL/6 male mice were treated with rolipram (1.25 mg/kg, i.p., twice a day for 5 consecutive days) to activate the cAMP/CREB pathway against cranial irradiation (2 Gy) , and were euthanized at 24 h post-irradiation. Exposure to γ-rays decreased both CREB phosphorylation and immunohistochemical markers for neurogenesis, including Ki-67 and doublecortin (DCX) , in the hippocampal dentate gyrus (DG) . However, the rolipram treatment protected from γ-irradiation-induced decreases of CREB phosphorylation, and Ki-67 and DCX immunoreactivity in the hippocampal DG. In an object recognition memory test, mice trained 24 h after acute γ-irradiation (2 Gy) showed significant memory impairment, which was attenuated by rolipram treatment. The results suggest that activation of CREB signaling ameliorates the detrimental effects of acute γ-irradiation on hippocampal neurogenesis and related functions in adult mice.