Ependyma in Neurodegenerative Diseases, Radiation-Induced Brain Injury and as a Therapeutic Target for Neurotrophic Factors.

The neuron loss caused by the progressive damage to the nervous system is proposed to be the main pathogenesis of neurodegenerative diseases. Ependyma is a layer of ciliated ependymal cells that participates in the formation of the brain-cerebrospinal fluid barrier (BCB). It functions to promotes the circulation of cerebrospinal fluid (CSF) and the material exchange between CSF and brain interstitial fluid. Radiation-induced brain injury (RIBI) shows obvious impairments of the blood-brain barrier (BBB). In the neuroinflammatory processes after acute brain injury, a large amount of complement proteins and infiltrated immune cells are circulated in the CSF to resist brain damage and promote substance exchange through the BCB. However, as the protective barrier lining the brain ventricles, the ependyma is extremely vulnerable to cytotoxic and cytolytic immune responses. When the ependyma is damaged, the integrity of BCB is destroyed, and the CSF flow and material exchange is affected, leading to brain microenvironment imbalance, which plays a vital role in the pathogenesis of neurodegenerative diseases. Epidermal growth factor (EGF) and other neurotrophic factors promote the differentiation and maturation of ependymal cells to maintain the integrity of the ependyma and the activity of ependymal cilia, and may have therapeutic potential in restoring the homeostasis of the brain microenvironment after RIBI or during the pathogenesis of neurodegenerative diseases.

Lycium barbarum Ameliorates Neural Damage Induced by Experimental Ischemic Stroke and Radiation Exposure.

Ischemic stroke and cranial radiotherapy may induce brain inflammatory response, oxidative stress, apoptosis and neuronal loss, and impairment of neurogenesis. Lycium barbarum has anti-oxidation, anti-inflammatory, anti-tumor and anti-aging properties, may produce both neuroprotective and radioprotective effects. In this narrative review paper, we described the neuroprotective effect of Lycium barbarum in different animal models of experimental ischemic stroke and limited studies in irradiated animal models. Relevant molecular mechanisms are also summarized. It has been shown that in experimental ischemic stroke models, Lycium barbarum produces neuroprotective effects by modulating neuroinflammatory factors such as cytokines and chemokines, reactive oxygen species, and neurotransmitter and receptor systems. In irradiation animal models, Lycium barbarum prevents radiation-induced loss of hippocampal interneurons. Given its minimal side-effects, these preclinical studies suggest that Lycium barbarum may be a promising radio-neuro-protective drug that can be used as an adjunct treatment to radiotherapy for brain tumor and in the treatment of ischemic stroke. At molecular levels, Lycium barbarum may regulate PI3K/Akt/GSK-3ß, PI3K/Akt/mTOR, PKCε/Nrf2/HO-1, keap1-Nrf2/HO-1, and NR2A and NR2B receptor- related signal transduction pathways to produce neuroprotective effects.

Dual Effects of miR-181b-2-3p/SOX21 Interaction on Microglia and Neural Stem Cells after Gamma Irradiation.

Ionizing radiation induces brain inflammation and the impairment of neurogenesis by activating microglia and inducing apoptosis in neurogenic zones. However, the causal relationship between microglial activation and the impairment of neurogenesis as well as the relevant molecular mechanisms involved in microRNA (miR) remain unknown. In the present study, we employed immunohistochemistry and real-time RT-PCR to study the microglial activation and miRNA expression in mouse brains. Real-time RT-PCR, western blot, ELISA, cell proliferation and cytotoxicity assay were used in BV2 and mouse neural stem cells (NSCs). In the mouse model, we found the acute activation of microglia at 1 day and an increased number of microglial cells at 1, 7 and 120 days after irradiation at postnatal day 3 (P3), day 10 (P10) and day 21 (P21), respectively. In cell models, the activation of BV2, a type of microglial cell line, was observed after gamma irradiation. Real-time RT-PCR analysis revealed a deceased expression of miR-181b-2-3p and an increased expression of its target SRY-related high-mobility group box transcription factor 21 (SOX21) in a dose- and time-dependent fashion. The results of the luciferase reporter assay confirmed that SOX21 was the target of miR-181b-2-3p. Furthermore, SOX21 knockdown by siRNA inhibited the activation of microglia, thereby suggesting that the direct interaction of 181b-2-3p with SOX21 might be involved in radiation-induced microglial activation and proliferation. Interestingly, the gamma irradiation of NSCs increased miR-181b-2-3p expression but decreased SOX21 mRNA, which was the opposite of irradiation-induced expression in BV2 cells. As irradiation reduced the viability and proliferation of NSCs, whereas the overexpression of SOX21 restored the impaired cell viability and promoted the proliferation of NSCs, the findings suggest that the radiation-induced interaction of miR-181b-2-3p with SOX21 may play dual roles in microglia and NSCs, respectively, leading to the impairment of brain neurogenesis.

Radiation-induced neuropathological changes in the oligodendrocyte lineage with relevant clinical manifestations and therapeutic strategies.

PURPOSE: With technological advancements in radiation therapy for tumors of the central nervous system (CNS), high doses of ionizing radiation can be delivered to the tumors with improved accuracy. Despite the reduction of ionizing radiation-induced toxicity to surrounding tissues of the CNS, a wide array of side effects still occurs, particularly late-delayed changes. These alterations, such as white matter damages and neurocognitive impairments, are often debilitative and untreatable, significantly affecting the quality of life of these patients, especially children. Oligodendrocytes, a major class of glial cells, have been identified to be one of the targets of radiation toxicity and are recognized be involved in late-delayed radiation-induced neuropathological changes. These cells are responsible for forming the myelin sheaths that surround and insulate axons within the CNS. Here, the effects of ionizing radiation on the oligodendrocyte lineage as well as the common clinical manifestations resulting from radiation-induced damage to oligodendrocytes will be discussed. Potential prophylactic and therapeutic strategies against radiation-induced oligodendrocyte damage will also be considered. CONCLUSION: Oligodendrocytes and oligodendrocyte progenitor cells (OPCs) are radiosensitive cells of the CNS. Here, general responses of these cells to radiation exposure have been outlined. However, several findings have not been consistent across various studies. For instance, cognitive decline in irradiated animals was observed to be accompanied by obvious demyelination or white matter changes in several studies but not in others. Hence, further studies have to be conducted to elucidate the level of contribution of the oligodendrocyte lineage to the development of late-delayed effects of radiation exposure, as well as to classify the dose and brain region-specific responses of the oligodendrocyte lineage to radiation. Several potential therapeutic approaches against late-delayed changes have been discussed, such as the transplantation of OPCs into irradiated regions and implementation of exercise. Many of these approaches show promising results. Further elucidation of the mechanisms involved in radiation-induced death of oligodendrocytes and OPCs would certainly aid in the development of novel protective and therapeutic strategies against the late-delayed effects of radiation.

The neuroprotective effects of icariin on ageing, various neurological, neuropsychiatric disorders, and brain injury induced by radiation exposure.

Epimedium brevicornum Maxim, a Traditional Chinese Medicine, has been used for the treatment of impotence, sinew and bone disorders, "painful impediment caused by wind-dampness," numbness, spasms, hypertension, coronary heart disease, menopausal syndrome, bronchitis, and neurasthenia for many years in China. Recent animal experimental studies indicate that icariin, a major bioactive component of epimedium may effectively treat Alzheimer's disease, cerebral ischemia, depression, Parkinson's disease, multiple sclerosis, as well as delay ageing. Our recent study also suggested that epimedium extract could exhibit radio-neuro-protective effects and prevent ionizing radiation-induced impairment of neurogenesis. This paper reviewed the pharmacodynamics of icariin in treating different neurodegenerative and neuropsychiatric diseases, ageing, and radiation-induced brain damage. The relevant molecular mechanisms and its anti-neuroinflammatory, anti-apoptotic, anti-oxidant, as well as pro-neurogenesis roles were also discussed.

Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms.

Population aging is occurring rapidly worldwide, challenging the global economy and healthcare services. Brain aging is a significant contributor to various age-related neurological and neuropsychological disorders, including Alzheimer's disease and Parkinson's disease. Several extrinsic factors, such as exposure to ionizing radiation, can accelerate senescence. Multiple human and animal studies have reported that exposure to ionizing radiation can have varied effects on organ aging and lead to the prolongation or shortening of life span depending on the radiation dose or dose rate. This paper reviews the effects of radiation on the aging of different types of brain cells, including neurons, microglia, astrocytes, and cerebral endothelial cells. Further, the relevant molecular mechanisms are discussed. Overall, this review highlights how radiation-induced senescence in different cell types may lead to brain aging, which could result in the development of various neurological and neuropsychological disorders. Therefore, treatment targeting radiation-induced oxidative stress and neuroinflammation may prevent radiation-induced brain aging and the neurological and neuropsychological disorders it may cause.

Neuroprotective Effects of Lycium barbarum Berry on Neurobehavioral Changes and Neuronal Loss in the Hippocampus of Mice Exposed to Acute Ionizing Radiation.

Background: Brain exposure to ionizing radiation during the radiotherapy of brain tumor or metastasis of peripheral cancer cells to the brain has resulted in cognitive dysfunction by reducing neurogenesis in hippocampus. The water extract of Lycium barbarum berry (Lyc), containing water-soluble Lycium barbarum polysaccharides and flavonoids, can protect the neuronal injury by reducing oxidative stress and suppressing neuroinflammation. Reseach Design: To demonstrate the long-term radioprotective effect of Lyc, we evaluated the neurobehavioral alterations and the numbers of NeuN, calbindin (CB), and parvalbumin (PV) immunopositive hippocampal neurons in BALB/c mice after acute 5.5 Gy radiation with/without oral administration of Lyc at the dosage of 10 g/kg daily for 4 weeks. Results: The results showed that Lyc could improve irradiation-induced animal weight loss, depressive behaviors, spatial memory impairment, and hippocampal neuron loss. Immunohistochemistry study demonstrated that the loss of NeuN-immunopositive neuron in the hilus of the dentate gyrus, CB-immunopositive neuron in CA1 strata radiatum, lacunosum moleculare and oriens, and PV-positive neuron in CA1 stratum pyramidum and stratum granulosum of the dentate gyrus after irradiation were significantly improved by Lyc treatment. Conclusion: The neuroprotective effect of Lyc on those hippocampal neurons may benefit the configuration of learning related neuronal networks and then improve radiation induced neurobehavioral changes such as cognitive impairment and depression. It suggests that Lycium barbarum berry may be an alternative food supplement to prevent radiation-induced neuron loss and neuropsychological disorders.

Spatiotemporal dynamics of γH2AX in the mouse brain after acute irradiation at different postnatal days with special reference to the dentate gyrus of the hippocampus.

Gamma H2A histone family member X (γH2AX) is a molecular marker of aging and disease. However, radiosensitivity of the different brain cells, including neurons, glial cells, cells in cerebrovascular system, epithelial cells in pia mater, ependymal cells lining the ventricles of the brain in immature animals at different postnatal days remains unknown. Whether radiation-induced γH2AX foci in immature brain persist in adult animals still needs to be investigated. Hence, using a mouse model, we showed an extensive postnatal age-dependent induction of γH2AX foci in different brain regions at 1 day after whole body gamma irradiation with 5Gy at postnatal day 3 (P3), P10 and P21. P3 mouse brain epithelial cells in pia mater, glial cells in white matter and cells in cerebrovascular system were more radiosensitive at one day after radiation exposure than those from P10 and P21 mice. Persistent DNA damage foci (PDDF) were consistently demonstrated in the brain at 120 days and 15 months after irradiation at P3, P10 and P21, and these mice had shortened lifespan compared to the age-matched control. Our results suggest that early life irradiation-induced PDDF at later stages of animal life may be related to the brain aging and shortened life expectancy of irradiated animals.

Early postnatal irradiation-induced age-dependent changes in adult mouse brain: MRI based characterization.

BACKGROUND: Brain radiation exposure, in particular, radiotherapy, can induce cognitive impairment in patients, with significant effects persisting for the rest of their life. However, the main mechanisms leading to this adverse event remain largely unknown. A study of radiation-induced injury to multiple brain regions, focused on the hippocampus, may shed light on neuroanatomic bases of neurocognitive impairments in patients. Hence, we irradiated BALB/c mice (male and female) at postnatal day 3 (P3), day 10 (P10), and day 21 (P21) and investigated the long-term radiation effect on brain MRI changes and hippocampal neurogenesis. RESULTS: We found characteristic brain volume reductions in the hippocampus, olfactory bulbs, the cerebellar hemisphere, cerebellar white matter (WM) and cerebellar vermis WM, cingulate, occipital and frontal cortices, cerebellar flocculonodular WM, parietal region, endopiriform claustrum, and entorhinal cortex after irradiation with 5 Gy at P3. Irradiation at P10 induced significant volume reduction in the cerebellum, parietal region, cingulate region, and olfactory bulbs, whereas the reduction of the volume in the entorhinal, parietal, insular, and frontal cortices was demonstrated after irradiation at P21. Immunohistochemical study with cell division marker Ki67 and immature marker doublecortin (DCX) indicated the reduced cell division and genesis of new neurons in the subgranular zone of the dentate gyrus in the hippocampus after irradiation at all three postnatal days, but the reduction of total granule cells in the stratum granulosun was found after irradiation at P3 and P10. CONCLUSIONS: The early life radiation exposure during different developmental stages induces varied brain pathophysiological changes which may be related to the development of neurological and neuropsychological disorders later in life.

Neuronal Development-Related miRNAs as Biomarkers for Alzheimer's Disease, Depression, Schizophrenia and Ionizing Radiation Exposure.

Radiation exposure may induce Alzheimer's disease (AD), depression or schizophrenia. A number of experimental and clinical studies suggest the involvement of miRNA in the development of these diseases, and also in the neuropathological changes after brain radiation exposure. The current literature review indicated the involvement of 65 miRNAs in neuronal development in the brain. In the brain tissue, blood, or cerebral spinal fluid (CSF), 11, 55, or 28 miRNAs are involved in the development of AD respectively, 89, 50, 19 miRNAs in depression, and 102, 35, 8 miRNAs in schizophrenia. We compared miRNAs regulating neuronal development to those involved in the genesis of AD, depression and schizophrenia and also those driving radiation-induced brain neuropathological changes by reviewing the available data. We found that 3, 11, or 8 neuronal developmentrelated miRNAs from the brain tissue, 13, 16 or 14 miRNAs from the blood of patient with AD, depression and schizophrenia respectively were also involved in radiation-induced brain pathological changes, suggesting a possibly specific involvement of these miRNAs in radiation-induced development of AD, depression and schizophrenia respectively. On the other hand, we noted that radiationinduced changes of two miRNAs, i.e., miR-132, miR-29 in the brain tissue, three miRNAs, i.e., miR- 29c-5p, miR-106b-5p, miR-34a-5p in the blood were also involved in the development of AD, depression and schizophrenia, thereby suggesting that these miRNAs may be involved in the common brain neuropathological changes, such as impairment of neurogenesis and reduced learning memory ability observed in these three diseases and also after radiation exposure.

Astroglial Connexins in Neurological and Neuropsychological Disorders and Radiation Exposure.

Radiotherapy is a common treatment for brain and spinal cord tumors and also a risk factor for neuropathological changes in the brain leading to different neurological and neuropsychological disorders. Astroglial connexins are involved in brain inflammation, development of Alzheimer's Disease (AD), depressive, epilepsy, and amyotrophic lateral sclerosis, and are affected by radiation exposure. Therefore, it is speculated that radiation-induced changes of astroglial connexins may be related to the brain neuropathology and development of neurological and neuropsychological disorders. In this paper, we review the functional expression and regulation of astroglial connexins expressed between astrocytes and different types of brain cells (including oligodendrocytes, microglia, neurons and endothelial cells). The roles of these connexins in the development of AD, depressive, epilepsy, amyotrophic lateral sclerosis and brain inflammation have also been summarized. The radiation-induced astroglial connexins changes and development of different neurological and neuropsychological disorders are then discussed. Based on currently available data, we propose that radiation-induced astroglial connexins changes may be involved in the genesis of different neurological and neuropsychological disorders which depends on the age, brain regions, and radiation doses/dose rates. The abnormal astroglial connexins may be novel therapeutic targets for the prevention of radiation-induced cognitive impairment, neurological and neuropsychological disorders.

Astroglial connexins in epileptogenesis.

The astroglial network connected through gap junctions assembling from connexins physiologically balances the concentrations of ions and neurotransmitters around neurons. Astrocytic dysfunction has been associated with many neurological disorders including epilepsy. Dissociated gap junctions result in the increased activity of connexin hemichannels which triggers brain pathophysiological changes. Previous studies in patients and animal models of epilepsy indicate that the reduced gap junction coupling from assembled connexin hemichannels in the astrocytes may play an important role in epileptogenesis. This abnormal cell-to-cell communication is now emerging as an important feature of brain pathologies and being considered as a novel therapeutic target for controlling epileptogenesis. In particular, candidate drugs with ability of inhibition of connexin hemichannel activity and enhancement of gap junction formation in astrocytes should be explored to prevent epileptogenesis and control epilepsy.

Epigenetic Regulation of the Hippocampus, with Special Reference to Radiation Exposure.

The hippocampus is crucial in learning, memory and emotion processing, and is involved in the development of different neurological and neuropsychological disorders. Several epigenetic factors, including DNA methylation, histone modifications and non-coding RNAs, have been shown to regulate the development and function of the hippocampus, and the alteration of epigenetic regulation may play important roles in the development of neurocognitive and neurodegenerative diseases. This review summarizes the epigenetic modifications of various cell types and processes within the hippocampus and their resulting effects on cognition, memory and overall hippocampal function. In addition, the effects of exposure to radiation that may induce a myriad of epigenetic changes in the hippocampus are reviewed. By assessing and evaluating the current literature, we hope to prompt a more thorough understanding of the molecular mechanisms that underlie radiation-induced epigenetic changes, an area which can be further explored.

Celastrol Alleviates Gamma Irradiation-Induced Damage by Modulating Diverse Inflammatory Mediators.

The present study aimed to explore the possible radioprotective effects of celastrol and relevant molecular mechanisms in an in vitro cell and in vivo mouse models exposed to gamma radiation. Human keratinocytes (HaCaT) and foreskin fibroblast (BJ) cells were exposed to gamma radiation of 20Gy, followed by treatment with celastrol for 24 h. Cell viability, reactive oxygen species (ROS), nitric oxide (NO) and glutathione (GSH) production, lipid peroxidation, DNA damage, inflammatory cytokine levels, and NF-κB pathway activation were examined. The survival rate, levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) in blood, and p65 and phospho-p65 expression were also evaluated in mice after exposure to gamma radiation and celastrol treatment. The gamma irradiation of HaCaT cells induced decreased cell viability, but treatment with celastrol significantly blocked this cytotoxicity. Gamma irradiation also increased free radical production (e.g., ROS and NO), decreased the level of GSH, and enhanced oxidative DNA damage and lipid peroxidation in cells, which were effectively reversed by celastrol treatment. Moreover, inflammatory responses induced by gamma irradiation, as demonstrated by increased levels of IL-6, TNF-α, and IL-1ß, were also blocked by celastrol. The increased activity of NF-κB DNA binding following gamma radiation was significantly attenuated after celastrol treatment. In the irradiated mice, treatment with celastrol significantly improved overall survival rate, reduced the excessive inflammatory responses, and decreased NF-κB activity. As a NF-κB pathway blocker and antioxidant, celastrol may represent a promising pharmacological agent with protective effects against gamma irradiation-induced injury.

Insights into Biological Role of LncRNAs in Epithelial-Mesenchymal Transition.

Long non-coding RNAs (lncRNAs) are versatile regulators of gene expression and play crucial roles in diverse biological processes. Epithelial-mesenchymal transition (EMT) is a cellular program that drives plasticity during embryogenesis, wound healing, and malignant progression. Increasing evidence shows that lncRNAs orchestrate multiple cellular processes by modulating EMT in diverse cell types. Dysregulated lncRNAs that can impact epithelial plasticity by affecting different EMT markers and target genes have been identified. However, our understanding of the landscape of lncRNAs important in EMT is far from complete. Here, we summarize recent findings on the mechanisms and roles of lncRNAs in EMT and elaborate on how lncRNAs can modulate EMT by interacting with RNA, DNA, or proteins in epigenetic, transcriptional, and post-transcriptional regulation. This review also highlights significant EMT pathways that may be altered by diverse lncRNAs, thereby suggesting their therapeutic potential.

The expanding roles of long non-coding RNAs in the regulation of cancer stem cells.

Long non-coding RNAs (lncRNAs) are a novel class of gene regulators playing multifaceted roles in physiological processes as well as pathological conditions such as cancer. Cancer stem cells (CSCs) are a small subset of tumor cells that constitute the origin and development of various malignant tumors. CSCs have been identified in a wide spectrum of human tumors and could act as a critical link underlying the processes of tumor metastasis and recurrence. Mounting evidence indicates that lncRNAs are aberrantly expressed in diverse CSCs and regulate CSC properties at different molecular levels. Here, we very briefly summarize the recent findings on the potential roles of lncRNAs in regulating various functions of CSCs, and elaborate on how can lncRNAs impact CSC properties via interacting with other macromolecules at the epigenetic, transcriptional, and post-transcriptional levels. This mini-review also highlights the understanding of the modular regulatory principles of lncRNA interactions in CSCs.

The Disparity of Impairment of Neurogenesis and Cognition After Acute or Fractionated Radiation Exposure in Adolescent BALB/c Mice.

The effect of acute X-ray irradiation with 2 Gy or fractionated exposure with 0.2 Gy continuously for 10 days (0.2 Gy × 10 = 2 Gy) was evaluated in the postnatal day 21 (P21) BALB/c mouse model. Both acute and fractionated irradiation induced impairment of cell proliferation and neurogenesis in the subgranular zone of the dentate gyrus labeled by Ki67 and doublecortin, respectively. Parvalbumin immunopositive interneurons in the subgranular zone were also reduced significantly. However, the 2 patterns of irradiation did not affect animal weight gain when measured at ages of P90 and P180 or 69 and 159 days after irradiation. Behavioral tests indicated that neither acute nor fractionated irradiation with a total dose of 2 Gy induced deficits in the contextual fear or spatial memory and memory for novel object recognition. Animal motor activity was also not affected in the open-field test. The disparity of the impairment of neurogenesis and unaffected cognition suggests that the severity of impairment of neurogenesis induced by acute or fractionated irradiation with a total dose of 2 Gy at P21 may not be worse enough to induce the deficit of cognition.

Radioprotective effect of epimedium on neurogenesis and cognition after acute radiation exposure.

The radioprotective effect of herb epimedium (or yin yang huo) extract (5 g/kg, oral administration daily for 4 weeks) on neurogenesis and cognition after acute radiation exposure with 5.5 Gy was evaluated in Balb/c mice by behavioral tests and immunohistochemical study. The results indicated that epimedium extract could improve animal weight loss, locomotor activity and spatial learning and memory which are similar to pre-irradiation intraperitoneal injection (100 mg/kg) of amifostine phosphate, a well- known radioprotective drug. Immunohistochemical study showed that epimedium extract prevented the loss of proliferation cells, newly generated neurons, and interneurons in the hilus, in particular, the subgranular zone of the dentate gyrus. It suggests that herb epimedium may be a promising radio-neuro-protective drug to prevent radiation-induced neuropsychological disorders.

Oleuropein induces apoptosis via abrogating NF-κB activation cascade in estrogen receptor-negative breast cancer cells.

Oleuropein is one of the most abundant phenolic compounds found in olives. Epidemiological studies have indicated that an increasing intake of olive oil can significantly reduce the risk of breast cancer. However, the potential effect(s) of oleuropein on estrogen receptor (ER)-negative breast cancer is not fully understood. This study aims to understand the anticancer effects and underlying mechanism(s) of oleuropein on ER-negative breast cancer cells in vitro. The effect of oleuropein on the viability of breast cancer cell lines was examined by mitochondrial dye-uptake assay, apoptosis by flow cytometric analysis, nuclear factor-κB (NF-κB) activation by DNA binding/reporter assays and protein expression by Western blot analysis. In the present report, thiazolyl blue tetrazolium bromide assay results indicated that oleuropein inhibited the viability of breast cancer cells, and its effects were more pronounced on MDA-MB-231 as compared with MCF-7 cells. It was further found that oleuropein increased the level of reactive oxygen species and also significantly inhibited cellular migration and invasion. In addition, the activation of NF-κB was abrogated as demonstrated by Western blot analysis, NF-κB-DNA binding, and luciferase assays. Overall, the data indicates that oleuropein can induce substantial apoptosis via modulating NF-κB activation cascade in breast cancer cells.

The Neuroprotective Effect of Amitriptyline on Radiation-Induced Impairment of Hippocampal Neurogenesis.

The radioprotective effect of amitriptyline, an inhibitor of acid sphingomyelinase (ASMase), on radiation-induced impairment of hippocampal neurogenesis, loss of interneuron, and animal weight changes was investigated in BALB/c mice by immunostaining of biomarkers for cell division (Ki67), immature neurons (doublecortin or DCX), and interneurons (parvalbumin or PV) in the dentate gyrus (DG) of hippocampus. The results indicated that preirradiation (with 10 mg/kg, 2 times per day, for 7 consecutive days) or postirradiation (with 10 mg/kg, 2 times per day, for 14 consecutive days) treatment (pretreatment or posttreatment) with intraperitoneal injection of amitriptyline prevented the loss of newly generated neurons, proliferating cells, and interneurons in the subgranular zone of the DG. At the molecular level, pretreatment or posttreatment inhibited the expression of sphingomyelin phosphodiesterase 1 (SMPD1) gene which codes for ASMase. The pretreatment for 7 days also prevented radiation-induced weight loss from 2 to 3 weeks, but not within 1 week after irradiation. On the other hand, the posttreatment with amitriptyline for 14 days could improve animal weight gain from 4 to 6 weeks after irradiation. The present study suggests that amitriptyline may be a promising candidate radio-neuroprotective drug to improve radiation-induced impairment of hippocampal neurogenesis and relevant neurological and neuropsychological disorders.