5 research outputs found
NF-κB and epigenetic mechanisms as integrative regulators of brain resilience to anoxic stress.
Activation of NF-kappaB p65/c-Rel dimer is associated with neuroprotection elicited by mGlu5 receptor agonists against MPP(+) toxicity in SK-N-SH cells.
c-Rel deficient mice, a mouse model of “spreading” PD-like pathology
Objectives: At premotor pathological stages, many PD patients suffer from nonmotor manifestations, including olfactory dysfunction and gastrointestinal constipation (1). In many PD cases synucleinopathy begins in defined nervous sites and progress in an anatomically predictable sequence, spreading from periphery (olfactory structures and enteric nervous system) to superior brain regions (2). NF-kB factors are cardinal players in the progression of the neurodegenerative process. In particular, the c-Rel subunit plays a crucial neuroprotective role, contributing to brain resilience to stress. We have previously shown that mice lacking c-Rel (c-rel-/- mice) develop with aging DA neuronal loss in substantia nigra pars compacta (SNc) with accumulation of aggregated alpha-synuclein, microglia activation and motor deficits responsive to L-DOPA administration (3). Methods: WT and c-rel-/- mice were studied at different ages with behavioral tests and biochemical /immunohistochemistry techniques. Moreover, levels and activity of c-Rel were analyzed in blood cells and brain samples of PD patients. Results: Already at a premotor pathology stage, c-rel-/- mice displayed olfactory and gastrointestinal dysfunctions, accumulation of alpha-synuclein in olfactory bulb as well as in the dorsal nucleus of vagus and locus coeruleus, striatal loss of dopamine transporter. Furthermore, the activity of the c-Rel protein decreased in the blood cells and SN of a considerable number of PD patients included in the study. Conclusions: c-rel-/- mice represent an innovative animal model to study pathological progression of PD and to investigate novel therapeutic approaches for early intervention in this pathology. Our recent data on humans suggest that c-Rel deficiency might be relevant also in the pathology of PD patients. References: 1. Simuni and Sethi. Ann Neurol 2008. 2. Braak et al. Cell Tissue Res 2004. 3. Baiguera et al. Brain 201