Yeonghoon Son

Neuropharmacological Potential of Gastrodia elata Blume and Its Components

Research has been conducted in various fields in an attempt to develop new therapeutic agents for incurable neurodegenerative diseases. Gastrodia elata Blume (GE), a traditional herbal medicine, has been used in neurological disorders as an anticonvulsant, analgesic, and sedative medication. Several neurodegenerative models are characterized by oxidative stress and inflammation in the brain, which lead to cell death via multiple extracellular and intracellular signaling pathways. The blockade of certain signaling cascades may represent a compensatory therapy for injured brain tissue. Antioxidative and anti-inflammatory compounds isolated from natural resources have been investigated, as have various synthetic chemicals. Specifically, GE rhizome extract and its components have been shown to protect neuronal cells and recover brain function in various preclinical brain injury models by inhibiting oxidative stress and inflammatory responses. The present review discusses the neuroprotective potential of GE and its components and the related mechanisms; we also provide possible preventive and therapeutic strategies for neurodegenerative disorders using herbal resources.

Hippocampal dysfunction during the chronic phase following a single exposure to cranial irradiation

Ionizing radiation can significantly affect brain functioning in adults. The present study assessed depression-like behaviors in adult C57BL/6 mice using the tail suspension test (TST) at 30 and 90days following a single cranial exposure to γ-rays (0, 1, or 10Gy) to evaluate hippocampus-related behavioral dysfunction during the chronic phase following cranial irradiation. Additionally, hippocampal neurogenesis, inflammatory cytokines, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) were analyzed. At 30 and 90days following irradiation with 10Gy, mice displayed significant depression-like behaviors. We observed a persistent decrease in the number of cells positive for doublecortin, an immunohistochemical marker for neurogenesis, in the hippocampus from 1 to 90days after irradiation with 10Gy. Changes in the mRNA expression of inflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor-α, IL-6, and interferon-γ, were not correlated with the decrease in hippocampal neurogenesis or the appearance of depression-like behavior during the chronic phase following irradiation. However, at 30 and 90days after irradiation with 10Gy, the number of microglia was significantly decreased compared with age-matched sham-irradiated controls. The reduction in the chronic phase was consistent with the significant down-regulation in the mRNA expression of iNOS, COX-2, BDNF, and GDNF in the hippocampus. Therefore, hippocampal dysfunction during the chronic phase following cranial irradiation may be associated with decreases in the neurogenesis- and synaptic plasticity-related signals, concomitant with microglial reduction in the hippocampus.

Hippocampal dysfunctions caused by cranial irradiation: a review of the experimental evidence.

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.

Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus

The brain can be exposed to ionizing radiation in various ways, and such irradiation can trigger adverse effects, particularly on learning and memory. However, the precise mechanisms of cognitive impairments induced by cranial irradiation remain unknown. In the hippocampus, brain-derived neurotrophic factor (BDNF) plays roles in neurogenesis, neuronal survival, neuronal differentiation, and synaptic plasticity. The significance of BDNF transcript variants in these contexts is becoming clearer. In the present study, both object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice were assessed 1 month after a single exposure to cranial irradiation (10 Gy) to evaluate hippocampus-related behavioral dysfunction following such irradiation. Furthermore, changes in the levels of BDNF, the cAMP-response element binding protein (CREB) phosphorylation, and BDNF transcript variants were measured in the hippocampus 1 month after cranial irradiation. On object recognition memory and contextual fear conditioning tasks, mice evaluated 1 month after irradiation exhibited significant memory deficits compared to sham-irradiated controls, but no apparent change was evident in locomotor activity. Both phosphorylated CREB and BDNF protein levels were significantly downregulated after irradiation of the hippocampus. Moreover, the levels of mRNAs encoding common BDNF transcripts, and exons IIC, III, IV, VII, VIII, and IXA, were significantly downregulated after irradiation. The reductions in CREB phosphorylation and BDNF expression induced by differential regulation of BDNF hippocampal exon transcripts may be associated with the memory deficits evident in mice after cranial irradiation.

Developmental and degenerative modulation of brain-derived neurotrophic factor transcript variants in the mouse hippocampus.

Brain‐derived neurotrophic factor (BDNF) is regarded as an important factor for neurogenesis, synaptic plasticity, and neuronal network organization in brain circuits. However, little is known about the regulation of BDNF transcript variants in the hippocampus during postnatal development and following chemically induced neurotoxicity. In the present study, we examined the expression of individual BDNF transcript variants in the mouse hippocampus on postnatal day (PD) 3, 7, 14, 21, and 56, as well as in the adult hippocampus 1, 2, 4, and 8 days after trimethyltin (TMT) treatment. During postnatal development, the expression levels of common BDNF‐coding transcripts and BDNF transcript variants increased gradually in the hippocampus, but the temporal patterns of each exon transcript showed significant differences. In the TMT‐treated hippocampus, the levels of common BDNF‐coding transcripts and exon I, IIC, III, VII, VIII, and IXA transcripts were significantly increased 1 day post‐treatment. These observations suggest that the differential regulation of BDNF exon transcripts may be associated with neuronal and synaptic maturation during postnatal development, and neuronal survival and synaptic plasticity in chemically induced neurodegeneration.

Glial activation with concurrent up-regulation of inflammatory mediators in trimethyltin-induced neurotoxicity in mice.

Trimethyltin (TMT), a potent neurotoxic chemical, causes dysfunction and neuroinflammation in the brain, particularly in the hippocampus. The present study assessed TMT-induced glial cell activation and inflammatory cytokine alterations in the mouse hippocampus, BV-2 microglia, and primary cultured astrocytes. In the mouse hippocampus, TMT treatment significantly increased the expression of glial cell markers, including the microglial marker ionized calcium-binding adapter molecule 1 and the astroglial marker glial fibrillary acidic protein. The expression of M1 and M2 microglial markers (inducible nitric oxide synthase [iNOS] and CD206, respectively) and pro-inflammatory cytokines (interleukin [IL]-1β, IL-6 and tumor necrosis factor [TNF]-α) were significantly increased in the mouse hippocampus following TMT treatment. In BV-2 microglia, iNOS, IL-1β, TNF-α, and IL-6 expression increased significantly, whereas arginase-1 and CD206 expression decreased significantly after TMT treatment in a time- and concentration-dependent manner. In primary cultured astrocytes, iNOS, arginase-1, IL-1β, TNF-α, and IL-6 expression increased significantly, whereas IL-10 expression decreased significantly after TMT treatment in a time- and concentration-dependent manner. These results indicate that significant up-regulation of pro-inflammatory signals in TMT-induced neurotoxicity may be associated with pathological processing of TMT-induced neurodegeneration.

Developmental and degenerative modulation of GABAergic transmission in the mouse hippocampus

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.

Nestin expression and glial response in the hippocampus of mice after trimethyltin treatment.

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.

β-Irradiation (166Ho patch)-induced skin injury in mini-pigs: effects on NF-κB and COX-2 expression in the skin.

In the present study, the detrimental effect of β-emission on pig skin was evaluated. Skin injury was modeled in mini-pigs by exposing the animals to 50 and 100 Gy of β-emission delivered by 166Ho patches. Clinicopathological and immunohistochemical changes in exposed skin were monitored for 18 weeks after β-irradiation. Radiation induced desquamation at 2~4 weeks and gradual repair of this damage was evident 6 weeks after irradiation. Changes in basal cell density and skin depth corresponded to clinically relevant changes. Skin thickness began to decrease 1 week after irradiation, and the skin was thinnest 4 weeks after irradiation. Skin thickness increased transiently during recovery from irradiation-induced skin injury, which was evident 6~8 weeks after irradiation. Epidermal expression of nuclear factor-kappa B (NF-κB) differed significantly between the untreated and irradiated areas. One week after irradiation, cyclooxygenase-2 (COX-2) expression was mostly limited to the basal cell layer and scattered among these cells. High levels of COX-2 expression were detected throughout the full depth of the skin 4 weeks after irradiation. These findings suggest that NF-κB and COX-2 play roles in epidermal cell regeneration following β-irradiation of mini-pig skin.

Treatment with granulocyte colony-stimulating factor aggravates thrombocytopenia in irradiated mice

Ionizing radiation can damage the hematopoietic system, and treatment with cytokines, including granulocytecolony-stimulating factor (G-CSF), is used to enhance hematopoietic recovery. In the present study, mice were whole-body irradiated with a sublethal dose of 5 Gy to produce severe myelosuppression and to evaluate the hematologic consequences of G-CSF treatment following irradiation. G-CSF (100 μg/kg of body weight) was injected immediately after irradiation, and then every three days for 3 weeks. G-CSF significantly ameliorated the decrease in peripheral neutrophils typically observed after exposure to radiation, but it also aggravated the decrease in the number of peripheral platelets during days 3–14 following irradiation. In the histological analysis, while the number of megakaryocytes was significantly decreased in the bone marrow, a number of trapped megakaryocytes were observed in the spleen of G-CSF-treated and irradiated mice. These data suggest that radiation-induced thrombocytopenia is worsened by G-CSF administration, possibly due to a decrease in the number of megakaryocytes in the bone marrow and an increase in the trapping of megakaryocytes in the spleen.