Astrogliosis

Reactive astrogliosis is a spectrum of changes in astrocytes that occur in response to all forms of CNS injury and disease. 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 hypertrophy, proliferation and scar formation. == Functions and effects ==

Reactive astrocytes may benefit or harm surrounding neural and non-neural cells. They undergo a series of changes that may alter astrocyte activities through gain or loss of functions lending to neural protection and repair, glial scarring, and regulation of CNS inflammation. such as uptake of potentially excitotoxic glutamate, adenosine release, and degradation of amyloid β peptides. Regulation of inflammation Reactive astrocytes are related to the normal function of astrocytes. Astrocytes are involved in the complex regulation of CNS inflammation that is likely to be context-dependent and regulated by multimodal extra- and intracellular signaling events. They have the capacity to make different types of molecules with either pro- or anti-inflammatory potential in response to different types of stimulation. Astrocytes interact extensively with microglia and play a key role in CNS inflammation. Reactive astrocytes can then lead to abnormal function of astrocytes and affect their regulation and response to inflammation. Pertaining to anti-inflammatory effects, reactive scar-forming astrocytes help reduce the spread of inflammatory cells during locally initiated inflammatory responses to traumatic injury or during peripherally-initiated adaptive immune responses. CNS injury responses have favored mechanisms that keep small injuries uninfected. Inhibition of the migration of inflammatory cells and infectious agents have led to the accidental byproduct of axon regeneration inhibition, owing to the redundancy between migration cues across cell types. == Biological mechanisms ==

Changes resulting from astrogliosis are regulated in a context-specific manner by specific signaling events that have the potential to modify both the nature and degree of these changes. Under different conditions of stimulation, astrocytes can produce intercellular effector molecules that alter the expression of molecules in cellular activities of cell structure, energy metabolism, intracellular signaling, and membrane transporters and pumps. Reactive astrocytes respond according to different signals and impact neuronal function. Molecular mediators are released by neurons, microglia, oligodendrocyte lineage cells, endothelia, leukocytes, and other astrocytes in the CNS tissue in response to insults ranging from subtle cellular perturbations to intense tissue injury. Transporters and channels The presence of astrocyte glutamate transporters is associated with a reduced number of seizures and diminished neurodegeneration whereas the astrocyte gap junction protein Cx43 contributes to the neuroprotective effect of preconditioning to hypoxia. In addition, AQP4, an astrocyte water channel, plays a crucial role in cytotoxic edema and aggravate outcome after stroke. == Neurological pathologies ==

Loss or disturbance of functions normally performed by astrocytes or reactive astrocytes during the process of reactive astrogliosis has the potential to underlie neural dysfunction and pathology in various conditions including trauma, stroke, multiple sclerosis, and others. Some of the examples are as follows: • Exacerbation of inflammation via cytokine production • Production and release of neurotoxic levels of reactive oxygen species • Release of potentially excitotoxic glutamate • The potential contribution to seizure genesis • Compromise of blood–brain barrier function as a result of vascular endothelial growth factor production • Cytotoxic edema during trauma and stroke through AQP4 overactivity • Potential for chronic cytokine activation of astrocytes to contribute to chronic pain Reactive astrocytes have the potential to promote neural toxicity via the generation cytotoxic molecules such as nitric oxide radicals and other reactive oxygen species, which may damage nearby neurons. Reactive astrocytes may also promote secondary degeneration after CNS injury. == Novel therapeutic techniques ==

Due to the destructive effects of astrogliosis, which include altered molecular expression, release of inflammatory factors, astrocyte proliferation and neuronal dysfunction, researchers are currently searching for new ways to treat astrogliosis and neurodegenerative diseases. Various studies have shown the role of astrocytes in diseases such as Alzheimer's, amyotrophic lateral sclerosis (ALS), Parkinson's, and Huntington's. Current studies are researching the possible benefits of inhibiting the inflammation caused by reactive gliosis in order to reduce its neurotoxic effects. Neurotrophins are currently being researched as possible drugs for neuronal protection, as they have been shown to restore neuronal function. For example, a few studies have used nerve growth factors to regain some cholinergic function in patients with Alzheimer's. BB14 was shown to reduce reactive astrogliosis following peripheral nerve injuries in rats by acting on DRG and PC12 cell differentiation. Although further research is needed, BB14 has the potential to treat a variety neurological diseases. Further research of neurotrophins could potentially lead to the development of a highly selective, potent, and small neurotrophin that targets reactive gliosis to alleviate some neurodegenerative diseases. Regulatory function of TGFB TGFB is a regulatory molecule involved in proteoglycan production. This production is increased in the presence of bFGF or Interleukin 1. An anti-TGFβ antibody may potentially reduce GFAP upregulation after CNS injuries, promoting axonal regeneration. Ethidium bromide treatment Injection of ethidium bromide kills all CNS glia (oligodendrocytes and astrocytes), but leaves axons, blood vessels, and macrophages unaffected. This provides an environment conducive to axonal regeneration for about four days. After four days, CNS glia reinvade the area of injection and axonal regeneration is consequently inhibited. This method has been shown to reduce glial scarring following CNS trauma. Metalloprotinease activity Oligodendrocyte precursor cells and C6 glioma cells produce metalloproteinase, which is shown to inactivate a type of inhibitory proteoglycan secreted by Schwann cells. Consequently, increased metalloproteinase in the environment around axons may facilitate axonal regeneration via degradation of inhibitory molecules due to increased proteolytic activity. == References ==