Exercise protects synaptic density in a rat model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including synaptic regeneration. OBJECTIVES: In a parkinsonian rat model, we test the hypotheses that exercise: (a) increases synaptic density and reduces neuroinflammation and (b) lowers the nociceptive threshold by increasing µ-opioid receptor expression. METHODS: Brain autoradiography was performed on rats unilaterally injected with either 6-hydroxydopamine (6-OHDA) or saline and subjected to treadmill exercise over 5 weeks. [3H]UCB-J was used to measure synaptic vesicle glycoprotein 2A (SV2A) density. Dopamine D2/3 receptor and µ-opioid receptor availability were assessed with [3H]Raclopride and [3H]DAMGO, respectively, while neuroinflammation was detected with the 18kDA translocator protein (TSPO) marker [3H]PK11195. The nociceptive threshold was determined prior to and throughout the exercise protocol. RESULTS: We confirmed a dopaminegic deficit with increased striatal [3H]Raclopride D2/3 receptor availability and reduced nigral tyrosine hydroxylase immunoreactivity in the ipsilateral hemisphere of all 6-OHDA-injected rats. Sedentary rats lesioned with 6-OHDA showed significant reduction of ipsilateral striatal and substantia nigra [3H]UCB-J binding while [3H]PK11195 showed increased ipsilateral striatal neuroinflammation. Lesioned rats who exercised had higher levels of ipsilateral striatal [3H]UCB-J binding and lower levels of neuroinflammation compared to sedentary lesioned rats. Striatal 6-OHDA injections reduced thalamic µ-opioid receptor availability but subsequent exercise restored binding. Exercise also raised thalamic and hippocampal SV2A synaptic density in 6-OHDA lesioned rats, accompanied by a rise in nociceptive threshold. CONCLUSION: These data suggest that treadmill exercise protects nigral and striatal synaptic integrity in a rat lesion model of PD - possibly by promoting compensatory mechanisms. Exercise was also associated with reduced neuroinflammation post lesioning and altered opioid transmission resulting in an increased nociceptive threshold.

The rpl23 gene and pseudogene are hotspots of illegitimate recombination in barley chloroplast mutator seedlings.

Previously, through a TILLING (Targeting Induced Local Lesions in Genomes) approach applied on barley chloroplast mutator (cpm) seedlings a high frequency of polymorphisms in the rpl23 gene was detected. All the polymorphisms corresponded to five differences already known to exist in nature between the rpl23 gene located in the inverted repeats (IRs) and the rpl23 pseudogene located in the large single copy region (LSC). In this investigation, polymorphisms in the rpl23 gene were verified and besides, a similar situation was found for the pseudogene in cpm seedlings. On the other hand, no polymorphisms were found in any of those loci in 40 wild type barley seedlings. Those facts and the independent occurrence of polymorphisms in the gene and pseudogene in individual seedlings suggest that the detected polymorphisms initially arose from gene conversion between gene and pseudogene. Moreover, an additional recombination process involving small recombinant segments seems to occur between the two gene copies as a consequence of their location in the IRs. These and previous results support the hypothesis that the CPM protein is a component of the plastome mismatch repair (MMR) system, whose failure of the anti-recombination activity results in increased illegitimate recombination between the rpl23 gene and pseudogene.

Sensory neuron and substance P involvement in symptoms of a zymosan-induced rat model of acute bowel inflammation.

Intestinal inflammation is a painful syndrome with multiple symptoms, including chronic pain. This study examined the possible role of sensory neurons and substance P in symptoms of an animal model of acute intestinal inflammation. The model was induced by injecting ethanol and zymosan into the colon of anesthetized male rats. Three hours later, sections of the colon were stained with hematoxylin and eosin. To determine the role of substance P, 5 mg/kg of the neurokinin-1 receptor (NK-1r) antagonist, CP-96,345, or 300 microg/kg of an antisense oligonucleotide targeted at NK-1r mRNA was administered. Spinal cord sections were examined for internalization of NK-1r, as an indicator of substance P release. Sections of colon revealed infiltration of inflammatory cells following ethanol and zymosan treatment. Plasma extravasation in rats given ethanol and zymosan was significantly greater than in controls given saline only (P<0.0001) or saline and ethanol (P<0.001). In ethanol- and zymosan-treated rats given CP-96,345, plasma extravasation was significantly less than in rats given ethanol and zymosan without the antagonist (P<0.0001). Administration of the antisense oligonucleotide also resulted in lower levels of plasma extravasation compared with controls (P<0.01). Internalization of the NK-1r was observed in neurons of lamina I in the T13-L2 and L6-S2 regions of the spinal cord, as well as in sympathetic preganglionic neurons at the L1 level. This internalization was observed in the absence of any other stimulus besides the inflammation itself. This study implicates substance P and its receptor, the NK-1r, in acute inflammation of the colon.

Fas-beyond death: a regenerative role for Fas in the nervous system.

Fas (CD95, APO-1), a member of the TNF superfamily, is a prototypical "death receptor" which transduces apoptotic signals in a variety of cell types. However, cell death is not the only possible outcome of Fas signalling. Fas engagement by Fas Ligand can also trigger proliferation or differentiation, promote tumour progression and angiogenesis, and induce cytokine secretion and integrin expression. Recently, we have reported that Fas engagement induces a potent regenerative response in sensory neurons in vitro, and enhances peripheral nerve regeneration in vivo. In contrast, other types of neurons, notably motoneurons, are acutely sensitive to Fas-induced apoptosis. Here, we review the literature on non-apoptotic Fas signalling pathways, and discuss the potential roles, molecular mechanisms, and regulators of Fas signalling in the nervous system.