Role Of Astrocytes In Pathogenesis Research Articles

Role of astrocytes in pathogenesis of ischemic brain injury.

Astrocytes play an important role in the homeostasis of the CNS both in normal conditions and after ischemic injury. The swelling of astrocytes is observed during and several seconds after brain ischemia. Then ischemia stimulates sequential morphological and biochemical changes in glia and induces its proliferation. Reactive astrocytes demonstrate stellate morphology, increased glial fibrillary acidic protein (GFAP) immunoreactivity, increased number of mitochondria as well as elevated enzymatic and non-enzymatic antioxidant activities. Astrocytes can re-uptake and metabolize glutamate and in this way they control its extracellular concentration. The ability of astrocytes to protect neurons against the toxic action of free radicals depends on their specific energy metabolism, high glutathione level, increased antioxidant enzyme activity (catalase, superoxide dismutase, glutathione peroxidase) and overexpression of antiapoptotic bcl-2 gene. Astrocytes produce cytokines (TNF-alpha, IL-1, IL-6) involved in the initiation and maintaining of immunological response in the CNS. In astrocytes, like in neurones, ischemia induces the expression of immediate early genes: c-fos, c-jun, fos B, jun B, jun D, Krox-24, NGFI-B and others. The protein products of these genes modulate the expression of different proteins, both destructive ones and those involved in the neuroprotective processes.

HIV-1 infection of the developing nervous system: central role of astrocytes in pathogenesis

Recent studies in our laboratory and that of Dr. Howard Gendelman have revealed two important pathways for neuronal damage during HIV-1 encephalopathy in children. First, substantial numbers of astrocytes are actively or latently infected with HIV-1. Astrocyte infection may lead to neuronal dysfunction through loss of supporting growth factors, excitotoxicity due to dysregulation of neurotransmitter reuptake, and loosening of the blood-brain barrier permitting further seeding of HIV-1 in the CNS. Significantly, infection of astrocytes is marked by near-exclusive synthesis of early regulatory gene products of HIV-1, while structural proteins characteristic of productive infection are found in macrophages, microglia and multinucleated giant cells. We propose the term ‘restricted’ to denote the non-productive infection found in astrocytes. Second, HIV-1-infected macrophages initiate inflammatory processes which are amplified through cell-cell interactions with astrocytes. Macrophage-astrocyte interactions produce arachidonic metabolites and potentially neurotoxic cytokines (TNF-α and IL-1β), leading to astroglial activation and proliferation which then amplifies these cellular processes. These new findings suggest that two major pathways leading to neurotoxicity in pediatric AIDS encephalopathy are linked to HIV-1 infection through astrocyte-mediated processes, and help explain how small numbers of productively infected cells indirectly cause widespread tissue pathology and elicit profound neurological impairment.