Stem cells and neurological disorders.
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Cell Differentiation↗
Biomedical subjects
Donald G Stein
Publications and source records attributed to Donald G Stein.
Progesterone protects against necrotic damage and behavioral abnormalities caused by traumatic brain injury.
A single injection of progesterone can attenuate cerebral edema when administered during the first 24 h after traumatic brain injury (TBI) in rats but this regimen may not always produce functional benefits. In this experiment, we sought to find the duration of progesterone administration needed to facilitate both behavioral and morphological recovery. Male rats received bilateral contusions of the medial prefrontal cortex and were given progesterone (4 mg/kg) or vehicle for 3 or 5 days postoperatively. Both the 3- and the 5-day progesterone regimens reduced the size of injury- induced necrosis and cell loss, with the 5-day schedule being most effective. With regard to behavioral outcome, only 5 days of progesterone injections resulted in improved spatial learning performance and reduced sensory neglect. These results show that 5 days of postinjury progesterone treatment are needed to reduce significantly the neuropathological and behavioral abnormalities found in a rodent model of TBI. These benefits of progesterone, in the absence of any known side effects, provide further support for clinical testing of this neurosteroid.
Animals↗
Fibronectin promotes survival and migration of primary neural stem cells transplanted into the traumatically injured mouse brain.
Multipotential stem cells are an attractive choice for cell therapy after traumatic brain injury (TBI), as replacement of multiple cell types may be required for functional recovery. In the present study, neural stem cells (NSCs) derived from the germinal zone of E14.5 GFP-expressing mouse brains were cultured as neurospheres in FGF2-enhanced medium. When FGF2 was removed in vitro, NSCs expressed phenotypic markers for neurons. astrocytes, and oligodendrocytes and exhibited migratory behavior in the presence of adsorbed fibronectin (FN). NSCs (10(5) cells) were transplanted into mouse brains 1 week after a unilateral, controlled, cortical contusion (depth = 1 mm, velocity = 6 m/s, duration = 150 ms) (n = 19). NSCs were injected either directly into the injury cavity with or without an injectable FN-based scaffold [collagen I (CnI)/FN gel; n = 14] or into the striatum below the injury cavity (n = 5). At all time points examined (1 week to 3 months posttransplant), GFP+ cells were confined to the ipsilateral host brain tissue. At 1 week, cells injected into the injury cavity lined the injury penumbra while cells inserted directly into the striatum remained in or around the needle track. Striatal transplants had a lower number of surviving GFP+ cells relative to cavity injections at the 1 week time point (p < 0.01). At the longer survival times (3 weeks-3 months), 63-76% of transplanted cells migrated into the fimbria hippocampus regardless of injection site, perhaps due to cues from the degenerating hippocampus. Furthermore, cells injected into the cavity within a FN-containing matrix showed increased survival and migration at 3 weeks (p < 0.05 for both) relative to injections of cells alone. These results suggest that FGF2-responsive NSCs present a promising approach for cellular therapy following trauma and that the transplant location and environment may play an important role in graft survival and integration.
Animals↗
Estrogen and progesterone as neuroprotective agents in the treatment of acute brain injuries.
Estrogen and progesterone are often thought of as steroid hormones that strongly influence reproductive and maternal behaviours. However, the steroids are now showing considerable promise as neuroprotective and neuroregenerative agents in stroke and traumatic brain injuries. Collectively, these two hormones have been reported to reduce the consequences of the injury cascade by enhancing anti-oxidant mechanisms, reducing excitotoxicity: altering glutamate receptor activity, reducing immune inflammation, providing neurotrophic support, stimulating axonal remyelinization and enhancing synaptogenesis and dendritic arborization. Estrogen has often been tried as a prophylactic treatment in females for ischemic brain injury, while progesterone has, thus far, been given as a post-injury treatment for both male and female subjects with acute, ischemic and traumatic injuries of the brain and spinal cord. This review compares and evaluates estrogen and progesterone as neuroactive agents in the acute treatment of brain damage caused by stroke and trauma.
Brain Edema↗
Developmental neurorehabilitation.
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Adolescent↗
Concepts of CNS plasticity in the context of brain damage and repair.
BACKGROUND: How effectively the brain can respond to injury and undergo structural repair has become one of the most exciting areas of contemporary basic and translational neuroscience research. Although there are no clinical treatments yet available to enhance repair of the damaged brain, there are a number of potential therapies being investigated. New drugs are designed to provide some degree of neuroprotection by preventing injured or vulnerable nerve cells from dying, or they are given in the hope of stimulating regenerative processes that could lead to the restoration or the formation of new connections that were lost because of the injury. MAIN OUTCOME MEASURES: The developments in pharmacology are based primarily upon understanding the molecular mechanisms of drug actions at the level of the genome or with respect to cellular metabolism. Although there is a substantial interest in the pharmacology of brain repair, there seems to be less concern with the various theories of central nervous system plasticity, organization, and reorganization after an injury. CONCLUSIONS: This review discusses some of the older and current ideas and theories that have been presented over the years to explain recovery of function. We then provide an overview of what is being done in the laboratory to develop new and safe drugs for the treatment of traumatic brain injuries.
Brain Injuries↗