RESUMEN
BACKGROUND: Cerebral Palsy (CP) is a major cause of motor and cognitive disability in children due to injury to the developing brain. Early intensive sensorimotor rehabilitation has been shown to change brain structure and reduce CP symptoms severity. We combined environmental enrichment (EE) and treadmill training (TT) to observe the effects of a one-week program of sensorimotor stimulation (EETT) in animals exposed to a CP model and explored possible mechanisms involved in the functional recovery. METHODS: Pregnant Wistar rats were injected with Lipopolysaccharide (LPS - 200 µg/kg) intraperitoneally at embryonic days 18 and 19. At P0, pups of both sexes were exposed to 20' anoxia at 37 °C. From P2 to P21, hindlimbs were restricted for 16 h/day during the dark cycle. EETT lasted from P21 to P27. TT - 15 min/day at 7 cm/s. EE - 7 days in enriched cages with sensorimotor stimulus. Functional 3D kinematic gait analysis and locomotion were analyzed. At P28, brains were collected for ex-vivo MRI and histological assessment. Neurotrophins and key proteins involved in CNS function were assessed by western blotting. RESULTS: CP model caused gross and skilled locomotor disruption and altered CNS neurochemistry. EETT reversed locomotor dysfunction with minor effects over gait kinematics. EETT also decreased brain inflammation and glial activation, preserved myelination, upregulated BDNF signaling and modulated the expression of proteins involved in excitatory synaptic function in the brain and spinal cord. CONCLUSIONS: Using this translational approach based on intensive sensorimotor rehabilitation, we highlight pathways engaged in the early developmental processes improving neurological recovery observed in CP.
RESUMEN
An increase in astrocyte reactivity has been described in Alzheimer's disease and seems to be related to the presence of a pro-inflammatory environment. Reactive astrocytes show an increase in the density of the 18 kDa translocator protein (TSPO), but TSPO involvement in astrocyte functions remains poorly understood. The goal of this study was to better characterize the mechanisms leading to the increase in TSPO under inflammatory conditions and the associated consequences. For this purpose, the C6 astrocytic cell line was used in the presence of lipopolysaccharide (LPS) or TSPO overexpression mediated by the transfection of a plasmid encoding TSPO. The results show that nonlethal doses of LPS induced TSPO expression at mRNA and protein levels through a STAT3-dependent mechanism and increased the number of mitochondria per cell. LPS stimulated reactive oxygen species (ROS) production and decreased glucose consumption (quantified by the [18F]FDG uptake), and these effects were diminished by FEPPA, a TSPO antagonist. The transfection-mediated overexpression of TSPO induced ROS production, and this effect was blocked by FEPPA. In addition, a synergistic effect of overexpression of TSPO and LPS on ROS production was observed. These data show that the increase of TSPO in astrocytic cells is involved in the regulation of glucose metabolism and in the pro-inflammatory response. These data suggest that the overexpression of TSPO by astrocytes in Alzheimer's disease would have rather deleterious effects by promoting the pro-inflammatory response.
RESUMEN
Apoptosis-dependent cell death of astrocytes has been described in Alzheimer's disease and is linked to the presence of two markers of the pathology: the ß-amyloid peptide (Aß) and the hyperphosphorylated Tau protein. Astrocytes also show reactive states characterized by the overexpression of the 18 kDa translocator protein (TSPO). However, TSPO is also known, in other areas of research, to participate in cell proliferation and death. Regulation of its function by autopolymerization has been described, but its involvement in apoptosis remains unknown. The aim was to determine the effects of Aß, Tau, and TSPO antagonists on proliferation/cell death and TSPO polymerization in the C6 astrocytic cell line. The dose-effect on cell death in response to Aß and Tau was observed but without alterations of TSPO density and polymerization. In contrast, nanomolar doses of antagonists stimulated cell proliferation, although micromolar doses induced cell death with a reduction in TSPO density and an increase in the ratio between the 36 and the 72 kDa TSPO polymers. Therefore, an alteration in the density and polymerization of TSPO appears to be related to cell death induced by TSPO antagonisms. In contrast, Aß- and Tau-induced death seems to be independent of TSPO alterations. In conclusion, even if its role in cell death and proliferation is demonstrated, TSPO seems to, in the context of Alzheimer's disease, rather represent a marker of the activity of astrocytes than of cell death.