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Microlesion stimulates neurogenesis. (a) Merged image of DCX and BrdU immunoreactive cells on the unlesioned control side (2 wks after the lesion). (b) Lesioned side illustrates increased DCX and BrdU (merged image). (c) Same as panel (b), but magnified; scale bar = 20 μm. Doublecortin (DCX) Immunoreactive cells in the subgranular zone of the dentate gyrus extend processes into the granular zone. The box inserted in (c) depicts confocal images of double-labeled DCX-BrdU cell at a higher power. Upper two panels are isolated for DCX (green) and BrdU (red) immunofluorescence, and the lower panel is the merged image ( scale bar = 10 μm). (d) Summary data of DCX signal expressed as percent of DG field. Lesioned side exhibits a significantly increased DCX signal compared to control at both 2 and 4 wks after the microlesion. Unlike microgliosis and astrocytosis, the DCX signal does not decline after 4 wks. (e) Cell counts of double-labeled immature neurons (DCX/BrdU) born within 2 days of lesion placement. The lesion significantly increased birth of new neurons compared to unlesioned control side. P < 0.001 . However, the number of double-labeled cells was significantly less at 4 wks than observed at 2 wks.
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We tested the hypothesis that transient microinjury to the brain elicits cellular and humoral responses that stimulate hippocampal neurogenesis. Brief stereotaxic insertion and removal of a microneedle into the right hippocampus resulted in (a) significantly increased expression of granulocyte-colony stimulating factor (G-CSF), the chemokine MIP-1a...
Citations
... Stab lesions of the hippocampus made by insertion and removal of an electrode or needle triggered an acute local rise in G-CSF and other cytokines released at the sites of insertion in the frontal cortex and hippocampus. 16 In addition, hippocampal neurogenesis was shown to be increased by the microlesion. The peak level of G-CSF in the hippocampus was reached at 6 h with return to baseline by 24 h. ...
... In the frontal cortex, G-CSF levels peaked at 12 h and also returned to baseline by 24 h. 16 From these results and the reports of others on the effects of G-CSF in stroke, 17,18 it was postulated that G-CSF may play an important role in the brain's repair response to injury. ...
INTRODUCTION: Treatment of traumatic brain injury (TBI) with granulocyte-colony stimulating factor (G-CSF) has been shown to enhance brain repair by direct neurotrophic actions on neural cells and by modulating the inflammatory response. Administration of cannabinoids after TBI has also been reported to enhance brain repair by similar mechanisms.
OBJECTIVES: The primary objective of this study was to test the hypothesis that G-CSF mediates brain repair by interacting with the endocannabinoid system (eCS). METHODS & RESULTS: 1) Mice that underwent controlled cortical impact (CCI) were treated with G-CSF for 3 days either alone or in the presence of CB1-R or CB2-R agonists and antagonists. The trauma resulted in decreased expression of CB1-R and increased expression of CB2-R in cortex, striatum and hippocampus. Cortical and striatal levels of the major endocannabinoid ligand 2-AG were also increased by the CCI. Administration of the hematopoietic cytokine G-CSF following TBI resulted in reversal of the trauma-induced CB1-R downregulation and reversal of CB2-R upregulation in the 3 brain regions. Treatment with CB1-R agonist (WIN55) or CB2-R agonist (HU308) mimicked the effects of G-CSF. 2) Pharmacological blockade of CB1-R or of CB2-R was not effective in preventing G-CSF’s reversal of the trauma-induced alterations in these receptors.
CONCLUSION: These results suggest that cellular and molecular mechanisms that mediate sub-acute effects of G-CSF do not depend on activation of CB1 or CB2 receptors. Failure of selective CB receptor antagonists to prevent the effects of G-CSF in this model has to be accepted with caution. CB receptor antagonists can interact with other CB and non-CB receptors. To eliminate the problem of non-specific interaction of CB receptor antagonists with other receptors, future experiments will utilize transgenic CB-1 R and in CB-2 R knockout mice and will be followed for longer intervals.
... However, even the presence of the electrode can significantly impact the neurochemical properties surrounding it. It is a foreign object that necessitates reaction from microglia and astrocytes that create an immediate inflammation and edema that subsides over the long term with the creation of a fibrotic membrane by astrocytes [24,25]. ...
... (C) A stereotactic arc is mounted on the frame set for the calculated target coordinates to implant the electrode in the desired are via a burr hole trephination. Furthermore, excitability is not only influenced by the threedimensional space and the position of the electrode, but also influenced by temporal aspects of stimulation as some effects of DBS happen within seconds, while others can take weeks to establish (Song et al, 2013;Reddy & Lozano, 2017). Lastly, the parameters of the stimulation itself (single pulse or continuous stimulation, amplitude, voltage, polarity, frequency, pulse width, pulse shape, rhythm) can vary and cause diverse electrical effects (Anderson et al, 2004;Kuncel & Grill, 2004;Montgomery & Gale, 2008;Carron et al, 2013). ...
... An animal study showed that implantation of a DBS electrode in the dorsal hippocampus has widespread and early effects on the brain even without electrical stimulation. The cellular effects were most pronounced after 2 weeks with microgliosis and astrocytosis; most of these cells were generated within 3 days after implantation (Song et al, 2013). The cytokine milieu showed expression of the pro-inflammatory cytokine IL-12, significant expression of granulocyte-colony-stimulating factor (G-CSF) along with increased expression of epidermal growth factor (EGF) and brain-derived neurotrophic factor (BDNF; Song et al, 2013). ...
... The cellular effects were most pronounced after 2 weeks with microgliosis and astrocytosis; most of these cells were generated within 3 days after implantation (Song et al, 2013). The cytokine milieu showed expression of the pro-inflammatory cytokine IL-12, significant expression of granulocyte-colony-stimulating factor (G-CSF) along with increased expression of epidermal growth factor (EGF) and brain-derived neurotrophic factor (BDNF; Song et al, 2013). Immunohistochemical staining showed an increased pattern of doublecortin (DCX) positive cells-a marker for immature neuronsindicating neurogenesis in the hippocampal subgranular zone (Song et al, 2013). ...
Deep brain stimulation (DBS) has been successfully used to treat movement disorders, such as Parkinson's disease, for more than 25 years and heralded the advent of electrical neuromodulation to treat diseases with dysregulated neuronal circuits. DBS is now superseding ablative techniques, such as stereotactic radiofrequency lesions. While serendipity has played a role in developing DBS as a therapy, research during the past two decades has shown that electrical neuromodulation is far more than a functional lesion that can be switched on and off. This understanding broadens the field to enable new types of stimulation, clinical indications , and research. This review highlights the complex effects of DBS from the single cell to the neuronal network. Specifically, we examine the electrical, cellular, molecular, and neurochemical mechanisms of DBS as applied to Parkinson's disease and other emerging applications.
... Direct interaction of G-CSF with its cognate receptor expressed on neural stem/progenitor cells results in proliferation and differentiation of neural progenitor cells (Schneider, Kruger, et al., 2005;. Increased neurogenesis triggered by G-CSF has been previously reported in other disease models and was replicated in the present study of TBI (Acosta et al., 2014;Sanchez-Ramos et al., 2009;Schneider, Kruger, et al., 2005;Song et al., 2013;Yang et al., 2010). In the present study, G-CSF treatment increased the CCI-triggered increase in DCX signal in dentate gyrus on the side of injury but not the contralateral side. ...
Purpose:
The overall objective was to elucidate cellular mechanisms by which G-CSF enhances recovery from traumatic brain injury in a hippocampal-dependent learning task.
Methods:
Chimeric mice were prepared by transplanting bone marrow cells that express green fluorescent protein (GFP+) from a transgenic "green" mice into C57BL/6 mice. Two months later, the animals sustained mild controlled cortical impact (CCI) to the right frontal-parietal cortex, followed by G-CSF (100μg/kg) treatment for 3 consecutive days. The primary behavioral end-point was performance on the radial arm water maze (RAWM) assessed before and after CCI (days 7 and 14). Secondary endpoints included a), motor performance on a rotating cylinder (rotarod), b) measurement of microglial and astroglial response, c) hippocampal neurogenesis, and d) measures of neurotrophic factors (BDNF, GDNF) in brain homogenates.
Results:
G-CSF treatment resulted in significantly better performance on the rotorod at one week, and in the RAWM after one and two weeks. The cellular changes found 2 wks after CCI in the G-CSF group included increased numbers of hippocampal newborn neurons as well as astrocytosis and microgliosis in striatum and frontal cortex on both sides of brain. GFP+ cells that co-labeled with Iba1 (microglial marker) comprised a significant proportion of striatal microglia in G-CSF treated animals, indicating the capacity of G-CSF to increase microglial recruitment to the site of injury. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF treated mice.
Conclusions:
G-CSF serves as a neurotrophic factor that increases hippocampal neurogenesis (or enhances survival of new-born neurons), and activates astrocytes and microglia. In turn, these activated glia release a plethora of cytokines and neurotrophic factors that contribute, in a poorly understood cascade, to the brain's repair response. G-CSF also acts directly on bone marrow-derived cells to enhance recruitment of microglia to the site of CCI from circulating monocytes to the site of CCI.
... Chemokines are essential mediators of posttraumatic neuroinflammation because of their ability to induce directional migration of circulating leukocytes, especially monocytes. A significant proportion of microglia has been reported to be derived from blood-borne monocytes that migrate across the injured blood–brain barrier and contribute to the microglial/macrophage population at the site of injury (Song et al., 2013). In that study, a brain lesion was produced by insertion and immediate removal of a fine acupuncture showed that treatment and time contributed significantly to total variation in the right hippocampus. ...
... When multiple t-tests were conducted (comparing vehicle with G-CSF at each time point) with Sidak's correction for multiple comparisons, the difference on day 4 between G-CSF and vehicle reached statistical significance (n 5 6 G-CSF-treated and n 5 6 vehicle-treated mice at each time point; P 5 0.02). needle through the cortex to the hippocampus (Song et al., 2013). The lesion triggered a microglial response in which approximately 26% of Iba-1 1 cells (microglia) were derived from circulating monocytes in the hippocampus and the frontal cortex. ...
... The lesion triggered a microglial response in which approximately 26% of Iba-1 1 cells (microglia) were derived from circulating monocytes in the hippocampus and the frontal cortex. In that same microlesion study, three of a panel of 17 cytokines were significantly elevated, peaking at 12 hr and returning to normal by 48 hr, with the exception of MIP-1a, which remained elevated (Song et al., 2013). By contrast, six cytokines that were modulated by G-CSF treatment following CCI in the present study were elevated on day 3, but only one of them remained altered by day 7, and all of them were no different from vehicle controls by day 14. ...
Hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) represent a novel approach for treatment of traumatic brain injury (TBI). After mild controlled cortical impact (CCI), mice were treated with G-CSF (100 μg/kg) for 3 consecutive days. The primary behavioral endpoint was performance on the radial arm water maze (RAWM), assessed 7 and 14 days after CCI. Secondary endpoints included 1) motor performance on a rotating cylinder (rotarod), 2) measurement of microglial and astroglial response, 3) hippocampal neurogenesis, and 4) measures of neurotrophic factors (brain-derived neurotrophic factor [BDNF] and glial cell line-derived neurotrophic factor [GDNF]) and cytokines in brain homogenates. G-CSF-treated animals performed significantly better than vehicle-treated mice in the RAWM at 1 and 2 weeks but not on the rotarod. Cellular changes found in the G-CSF group included increased hippocampal neurogenesis as well as astrocytosis and microgliosis in both the striatum and the hippocampus. Neurotrophic factors GDNF and BDNF, elaborated by activated microglia and astrocytes, were increased in G-CSF-treated mice. These factors along with G-CSF itself are known to promote hippocampal neurogenesis and inhibit apoptosis and likely contributed to improvement in the hippocampal-dependent learning task. Six cytokines that were modulated by G-CSF treatment following CCI were elevated on day 3, but only one of them remained altered by day 7, and all of them were no different from vehicle controls by day 14. The pro- and anti-inflammatory cytokines modulated by G-CSF administration interact in a complex and incompletely understood network involving both damage and recovery processes, underscoring the dual role of inflammation after TBI. © 2016 Wiley Periodicals, Inc.
... We cannot rule out the possibility that electrode insertion plays a role in the observed findings given that any puncture injury to the brain elicits a short-term (up to about 14 days) proliferative response. However, we have studied the brain of PD-DBS patients that died some considerable time (ranging from 0.5 to 6 years) after electrode placement, and thus, it is unlikely that the increase in progenitor proliferation is a result of the initial surgical intervention [28,29]. We also cannot rule out the possibility that chronic electrode placement leads to the proliferative response seen. ...
Deep brain stimulation (DBS) has been used for more than a decade to treat Parkinson's disease (PD); however, its mechanism of action remains unknown. Given the close proximity of the electrode trajectory to areas of the brain known as the "germinal niches," we sought to explore the possibility that DBS influences neural stem cell proliferation locally, as well as more distantly.
We studied the brains of a total of 12 idiopathic Parkinson's disease patients that were treated with DBS (the electrode placement occurred 0.5-6 years before death), and who subsequently died of unrelated illnesses. These were compared to the brains of 10 control individuals without CNS disease, and those of 5 PD patients with no DBS.
Immunohistochemical analyses of the subventricular zone (SVZ) of the lateral ventricles, the third ventricle lining, and the tissue surrounding the DBS lead revealed significantly greater numbers of proliferating cells expressing markers of the cell cycle, plasticity, and neural precursor cells in PD-DBS tissue compared with both normal brain tissue and tissue from PD patients not treated with DBS. The level of cell proliferation in the SVZ in PD-DBS brains was 2-6 fold greater than that in normal and untreated PD brains.
Our data suggest that DBS is capable of increasing cellular plasticity in the brain, and we hypothesize that it may have more widespread effects beyond the electrode location. It is unclear whether these effects of DBS have any symptomatic or other beneficial influences on PD.
Deep Brain Stimulation (DBS) has become a pivotal therapeutic approach for Parkinson's Disease (PD) and various neuropsychiatric conditions, impacting over 200,000 patients. Despite its widespread application, the intricate mechanisms behind DBS remain a subject of ongoing investigation. This article provides an overview of the current knowledge surrounding the local, circuit, and neurobiochemical effects of DBS, focusing on the subthalamic nucleus (STN) as a key target in PD management.
The local effects of DBS, once thought to mimic a reversible lesion, now reveal a more nuanced interplay with myelinated axons, neurotransmitter release, and the surrounding microenvironment. Circuit effects illuminate the modulation of oscillatory activities within the basal ganglia and emphasize communication between the STN and the primary motor cortex. Neurobiochemical effects, encompassing changes in dopamine levels and epigenetic modifications, add further complexity to the DBS landscape.
Finally, within the context of understanding the mechanisms of DBS in PD, the article highlights the controversial question of whether DBS exerts disease-modifying effects in PD. While preclinical evidence suggests neuroprotective potential, clinical trials such as EARLYSTIM face challenges in assessing long-term disease modification due to enrollment timing and methodology limitations. The discussion underscores the need for robust biomarkers and large-scale prospective trials to conclusively determine DBS's potential as a disease-modifying therapy in PD.
Deep brain stimulation has revolutionized the treatment of movement disorders and is gaining momentum in the treatment of several other neuropsychiatric disorders. In almost all applications of this therapy, the insertion of electrodes into the target has been shown to induce some degree of clinical improvement prior to stimulation onset. Disregarding this phenomenon, commonly referred to as “insertional effect”, can lead to biased results in clinical trials, as patients receiving sham stimulation may still experience some degree of symptom amelioration. Similar to the clinical scenario, an improvement in behavioural performance following electrode implantation has also been reported in preclinical models. From a neurohistopathologic perspective, the insertion of electrodes into the brain causes an initial trauma and inflammatory response, the activation of astrocytes, a focal release of gliotransmitters, the hyperexcitability of neurons in the vicinity of the implants, as well as neuroplastic and circuitry changes at a distance from the target. Taken together, it would appear that electrode insertion is not an inert process, but rather, triggers a cascade of biological processes, and, as such, should be considered alongside the active delivery of stimulation, as an active part of the deep brain stimulation therapy.
Reactive Oxygen Species are chemically unstable molecules generated during aerobic respiration, especially in the electron transport chain. ROS are involved in various biological functions; any imbalance in their standard level results in severe damage, for instance, oxidative damage, inflammation in a cellular system, and cancer. Oxidative damage activates signaling pathways, which result in cell proliferation, oncogenesis, and metastasis. Since the last few decades, mesenchymal stromal cells have been explored as therapeutic agents against various pathologies, such as cardiovascular diseases, acute and chronic kidney disease, neurodegenerative diseases, macular degeneration, and biliary diseases. Recently, the research community has begun developing several anti-tumor drugs, but these therapeutic drugs are ineffective. In this present review, we would like to emphasize MSCs-based targeted therapy against pathologies induced by ROS as cells possess regenerative potential, immunomodulation, and migratory capacity. We have also focused on how MSCs can be used as next-generation drugs with no side effects.
