Toxic organic cations can damage nigrostriatal dopaminergic pathways as seen in most parkinsonian syndromes and in some cases of illicit drug exposure. Here, we show that the organic cation transporter 3 (Oct3) is expressed in nondopaminergic cells adjacent to both the soma and terminals of midbrain dopaminergic neurons. We hypothesized that Oct3 contributes to the dopaminergic damage by bidirectionally regulating the local bioavailability of toxic species. Consistent with this view, Oct3 deletion and pharmacological inhibition hampers the release of the toxic organic cation 1-methyl-4-phenylpyridinium from astrocytes and protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration in mice. Furthermore, Oct3 deletion impairs the removal of the excess extracellular dopamine induced by methamphetamine and enhances striatal dopaminergic terminal damage caused by this psychostimulant. These results may have far-reaching implications for our understanding of the mechanism of cell death in a wide range of neurodegenerative diseases and may open new avenues for neuroprotective intervention.astrocytes ͉ Parkinson's disease ͉ extraneuronal monoamine transporter ͉ dopamine ͉ methamphetamine
While GM1 may interact with α-synuclein
in vitro
to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity
in vivo
has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN dopamine neurons and striatal dopamine levels, reduced α-synuclein aggregation, and delayed start administration of GM1 reversed early appearing behavioral deficits. These results extend prior positive results in MPTP models, are consistent with the results of a small clinical study of GM1 in PD patients that showed slowing of symptom progression with chronic use, and argue for the continued refinement and development of GM1 as a potential disease modifying therapy for PD.
Caspases, a family of cysteine proteases, are widely activated in neurons and glia in the injured brain, a response thought to induce apoptosis. However, caspase activation in astrocytes following injury is not strongly associated with apoptosis. The present study investigates the potential role of caspase activation in astrocytes with another characteristic response to neural injury, astrogliosis. Caspase activity and morphological and biochemical indices of astrogliosis and apoptosis were assessed in (i) cultured neonatal rat astrocytes treated with astrogliosis-inducing stimuli (dibutryl cAMP, β-amyloid peptide), and (ii) cultures of adult rat hippocampal astrocytes generated from control and kainate-lesioned rats. The effects of broad spectrum and specific pharmacological caspase inhibitors were assessed on indicators of astrogliosis, including stellate morphology and expression of glutamine synthetase and fibroblast growth factor-2. Reactive neonatal and adult astrocytes demonstrated an increase in total caspase activity with a corresponding increase in the expression of active caspase-3 in the absence of cell death. Broad spectrum caspase inhibition with zVAD significantly attenuated increases in glutamine synthetase and fibroblast growth factor-2 in the reactive astrocytes. In the reactive neonatal astrocyte cultures, specific inhibition of caspases-3 and -11 also attenuated glutamine synthetase and fibroblast growth factor-2 expression, but did not reverse the morphological reactive phenotype. Astrogliosis is observed in all forms of brain injury and despite extensive study, its molecular triggers remain largely unknown. While previous studies have demonstrated active caspases in astrocytes following acute brain injury, here we present evidence functionally implicating the caspases in astrogliosis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.