Abstract The central nervous system CNS is prone to heterogeneous insults of diverse etiologies that elicit multifaceted responses. Acute and focal injuries trigger wound repair with tissue replacement. Diffuse and chronic diseases provoke gradually escalating tissue changes. The responses to CNS insults involve complex interactions among cells of numerous lineages and functions, including CNS intrinsic neural cells, CNS intrinsic non-neural cells, and CNS extrinsic cells that enter from the circulation. The contributions of diverse non-neuronal cell types to outcome after acute injury, or to the progression of chronic disease, are of increasing interest as the push towards understanding and ameliorating CNS afflictions accelerates.
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Main article: Astrogliosis Micrograph showing gliosis in the cerebellum. Reactive astrocytes on the left display severe proliferation and domain overlap. Reactive astrogliosis is the most common form of gliosis and involves the proliferation of astrocytes , a type of glial cell responsible for maintaining extracellular ion and neurotransmitter concentrations, modulating synapse function, and forming the blood—brain barrier.
Although the mechanisms which lead to astrogliosis are not fully understood, neuronal injury is well understood to cause astrocyte proliferation, and astrogliosis has long been used as an index for neuronal damage.
Although this hypertrophy and proliferation in their extreme form are most closely associated with the formation of a glial scar , astrogliosis is not an all-or-none process in which a glial scar forms. In fact, it is a spectrum of changes that occur based on the type and severity of central nervous system CNS injury or disease triggering the event. Reactive astrocytes are affected by molecular signals released from a variety of CNS cell types including neurons, microglia , oligodendrocyte precursor cells , leukocytes, endothelia, and even other astrocytes.
Some of the many signalling molecules used in these pathways include the cytokines interleukin 6 IL-6 , ciliary neurotrophic factor CNTF , and leukemia inhibitory factor LIF.
A few of the most important effects of astrogliosis are listed below. Neuroprotective effects — Reactive astrocytes release neurotrophic factors , such as glial cell-derived neurotrophic factor GDNF , which protects against programmed cell death Maintenance of the extracellular environment — Astrocytes are responsible for the uptake of glutamate , which restricts excitotoxicity to neurons and other cell types, as well as the elimination of free radicals   Release of anti-inflammatory molecules Restoration of blood brain barrier function Seclusion of the injury site and containment of infection from healthy tissue  Detrimental effects[ edit ] Restriction of axon regeneration — In cases of glial scar formation, reactive astrocytes enmesh the lesion site and deposit an inhibitory extracellular matrix consisting of chondroitin sulfate proteoglycans.
The dense structure of these proteins is a physically and chemically inhibitory barrier to axon regeneration and the reestablishment of axon connections. Unlike other glial cell types, microglia are extremely sensitive to even small changes in the cellular environment, allowing for a rapid response to inflammatory signals and prompt destruction of infectious agents before sensitive neural tissue can be damaged.
Microgliosis following a CNS insult most commonly involves the development of an altered cellular morphology, specifically the enlargement of cellular processes. Within the first week following the injury, microglia begin to proliferate abnormally and while doing so exhibit several immunophenotypic changes, particularly an increased expression of MHC antigens.
For example, active microglia are the primary effectors of innate immunity and fulfill this role by phagocyting the proteins of dead neurons, presenting antigens at their surface, and producing a variety of pro-inflammatory cytokines and toxic molecules that compromise the survival of surrounding neurons which may be similarly damaged or infected.
Because various characteristics of microgliosis occur in different time frames after the initial triggering insult, microgliosis must depend on mechanisms which fluctuate temporally based on injured neuronal signals. Studies have shown that in cases of reversible neuronal injury, such as axotomy , neuron signals cause microglia to produce trophic factors, which promote neuron survival.
In cases of irreversible injury, however, microglia are induced to release neurotoxic factors that promote increased degeneration of the neuron and more rapid phagocytosis by the microglia. Unlike the microglial response, which occurs rapidly, the start of astrogliosis is often delayed. A likely cause of this relationship is the pro-inflammatory cytokines and chemokines released at elevated levels by microglia upon activation.
Astrocytes themselves also produce cytokines, which may be used for self-regulation or for the regulation of microglia, which contain similar cytokine receptors. This phenomenon creates a feedback loop , allowing both microglia and astrocytes to regulate one another. In addition, evidence suggests microglial regulation of astrogliosis may also include inhibitory effects.
Reduced levels of microgliosis have been associated with reduced astrocyte numbers, which also suggests that microglia are important regulators of the degree of astrocyte activation. Unlike astrocytes and microglia, oligodendrocytes undergo a much more limited reaction to injury. In all cases, however, some oligodendrocytes are lost, through necrosis or apoptosis , while others survive and may form part of the glial scar along with myelin debris.
Some of these cells may produce new myelin when exposed to signals from activated microglia and astrocytes. These molecules, notably IL-1, initiate an inflammatory response in various cells including astrocytes that contributes to the gliosis reaction.
In culture, both molecules act as mitogens , prompting the proliferation of astrocytes. Gliosis in any form entails an alteration in cellular activity that has the potential to create widespread effects on neurons as well as other non-neural cells, causing either a loss of normal functions or a gain of detrimental ones.
CNS trauma[ edit ] Acute trauma to the brain or spinal cord results in gliosis, most often in its severe form with the development of a glial scar. Different locations around the lesion site may exhibit different severities of gliosis; for example, a glial scar at the location of damaged tissue may be surrounded by areas with less severe astrocyte proliferation or hypertrophy.
Diffuse traumatic injury can result in diffuse or more moderate gliosis without scar formation. In such cases, gliosis may also be reversible. In all instances of gliosis resulting from CNS trauma, the long-term clinical outcome is highly dependent on the degree of astrogliosis and scar formation.
These astrocytes often exhibit extreme hypertrophy and multiple distinct nuclei , and their production of pro-inflammatory molecules has been implicated in several inflammatory disorders.
Upon retinal injury, gliosis of these cells occurs, functioning to repair damage, but often having harmful consequences in the process, worsening some of the diseases or problems that initially trigger it. A study compared the effects of two glial toxins, AAA and Neurostatin, on retinal gliosis in mice. AAA did not inhibit the production of protease by astrocytes, and so did not prevent ganglion cell apoptosis.
However, Neurostatin successfully inhibited activation of astrocytes, in turn decreasing retinal ganglion cell death significantly. Neurostatin is also effective in the inhibition of other glial cells, and may be an area of interest in the treatment of degenerative diseases such as glaucoma.
Sometimes mistaken for an intraocular tumor, MRG can arise from a neurodegenerative disease, congenital defect, or from trauma to the eyeball, sometimes appearing years after such an incident. Gliosis and glial scarring occur in areas surrounding the amyloid plaques which are hallmarks of the disease, and postmortem tissues have indicated a correlation between the degree of astrogliosis and cognitive decline.
Reactive astrocytes have been implicated in this condition through either a loss of their neuroprotective ability or through the gain of neurotoxic effects. Late stages of ALS are also characterized by significant astrogliosis and astrocyte proliferation around areas of degeneration.
Because gliosis is a dynamic process which involves a spectrum of changes depending on the type and severity of the initial insult, to date, no single molecular target has been identified which could improve healing in all injury contexts.
Rather, therapeutic strategies for minimizing the contribution of astrogliosis to CNS pathologies must be designed to target specific molecular pathways and responses. Other proposed targets related to astrogliosis include manipulating AQP4 channels, diminishing the action of NF-kB , or regulating the STAT3 pathway in order to reduce the inflammatory effects of reactive astrocytes.
One notable microglial activation inhibitor is minocycline , which is a known suppressor of astrogliosis.
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Nikasa Chronic vocal tic disorder; Tic — chronic motor tic disorder However, chronic gastritis is still one of the most common serious pandemic infections with such severe killing sequelae as peptic ulcer or gastric cancer. In this work, we analyzed the cellular and molecular changes in the adult brain occurring with the development of experimental hypothyroidism. Supporting Self-management of Chronic Pain. We found that CRS induced anxiety and depression-like behaviors, impaired the formation and facilitated the extinction process in morphine-induced conditioned place preference CPPand also blocked morphine-induced behavioral sensitization. However, the role of ghrelin in opioid effects has rarely been examined. Combination treatment with dipyridamole, aspirin, and tPA in an embolic model of stroke in rats. In Case 1 and 3, no pallidal lesions believed to be the most common lesion of the gray matter in CO poisoning were found in the serial X-ray CT scans.
Reactive gliosis and the multicellular response to CNS damage and disease
Maunris Investigations to achieve a diagnosis for chronic diarrhea range from screening blood and stool tests to more directed testing reactvia as diagnostic imaging, and endoscopic and histological evaluation. Obsessive-compulsive disorder; chronic versus non- chronic symptoms. Changes due to reactive astrogliosis vary with the severity of the CNS insult along a graduated continuum of progressive alterations in molecular expression, progressive cellular hypertrophyproliferation and scar formation. Opioid drugs are used in the treatment of acute post-surgical pain and chronic pain, such as those associated with cancer.