Animal models are invaluable tools to study neurodegenerative disorders but a general consensus on the most accurate rodent model of Parkinson's disease has not been reached. Here, we examined how different methods of MPTP administration influence the degeneration of the dopaminergic (DA) system. Adult male C57BL/6 mice were treated with the same cumulative dose of MPTP following four distinct procedures: (i) subacute i.p. injections; (ii) 28-day chronic s.c. infusion; (iii) 28-day chronic i.p. infusion; and (iv) 14-day chronic i.p. infusion. Subacute MPTP treatment significantly affected all aspects of the DA system within the nigral and striatal territories. In contrast, the 28-day chronic s.c. infusion did not significantly alter any components of the DA system. The 28-and 14-day chronic i.p. infusions induced loss of tyrosine hydroxylase (TH)-positive cells correlated with a decrease in Nurr1 mRNA levels, but no significant decrease in the density of TH striatal fibers. Importantly, however, only the 14-day chronic MPTP i.p. infusion protocol promoted the formation of neuronal inclusions as noted by the expression of a-synuclein protein within the cytoplasm of TH nigral neurons. Overall, we found that the 14-day chronic MPTP i.p. infusion reproduces more accurately the pathological characteristics of early stage Parkinson's disease.

Background-The prevalence of native coronary chronic total occlusions (CTOs) after coronary artery bypass grafts (CABGs) is higher than in non-CABG population. We examined outcomes of CTO percutaneous coronary intervention (PCI) post-CABG versus without CABG. Then, we looked at feasibility and outcomes of retrograde CTO PCI via patent or occluded saphenous vein graft. Methods and Results-We compared patient and procedural characteristics of 470 CTO cases treated from January 2010 to December 2015 depending on history of CABG. We assessed major adverse cardiac events, including cardiac death, myocardial infarction, ischemia-driven target-vessel revascularization, or reocclusion 1 year after successful CTO PCI in patients treated before February 2015. Post-CABG patients (175 cases) had a higher J-CTO score (2.5 versus 2.1; P=0.002). In-hospital complications were similar, although the incidence of contrast-induced nephropathy was higher in post-CABG patients (4.6% versus 1%; P=0.01). With multivariable analysis, post-CABG status was associated with higher incidence of 1-year major adverse cardiac event (hazards ratio=2.2; P=0.02). As a second level analysis, we looked at the feasibility and safety of CTO PCI via saphenous vein grafts (19% of post-CABG cases) versus collateral channels (36%) versus with an antegrade-only approach (45%), and assessed short-term outcomes and complications. High success was achieved in the saphenous vein graft group. In-hospital events were similar in the 3 groups. Conclusions-Post-CABG CTO PCI is associated with similar high success and low complications compared with CTO PCI in patients who never had CABG. However, it is associated with higher recurrent events at 1 year. To achieve high success rate, use of saphenous vein grafts as retrograde conduits seems to be safe and effective. (Circ Cardiovasc Interv. 2016;9:e003515.

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Septal surfing is a safe and highly successful technique for crossing septal CCs when a retrograde approach is mandated for CTO PCI. The Werner class does not affect retrograde CC crossing success or time.

Cystamine has shown significant neuroprotective properties in preclinical studies of Parkinson's disease (PD) and Huntington's disease (HD). Cysteamine, its FDA-approved reduced form, is scheduled to be tested for clinical efficacy in HD patients. Here, we studied the key cystamine metabolites, namely cysteamine, hypotaurine and taurine, as well as cysteine, in order to identify which one is more distinctively responsible for the neuroprotective action of cystamine. After a single administration of cystamine (10, 50 or 200 mg/kg), naïve mice were perfused with phosphate-buffered saline (PBS) at 1, 3, 12, 24 or 48 h post-injection and brain and plasma samples were analyzed by two distinct HPLC methods. Although plasma levels remained under the detection threshold, significant increases in cysteamine brain levels were detected with the 50 and 200 mg/kg doses in mice perfused 1 and 3 h following cystamine injection. To further assess cysteamine as the candidate molecule for pre-clinical and clinical trials in PD, we evaluated its capacity to cross the blood brain barrier. Using an in situ cerebral perfusion technique, we determined that the brain transport coefficient (Clup) of cysteamine (259 lM) was 0.15 ± 0.02 lL/g/s and was increased up to 0.34 ± 0.07 lL/g/s when co-perfused in the presence of cysteine. Taken together, these results strongly suggest that cysteamine is the neuroactive metabolite of cystamine and may further support its therapeutic use in neurodegenerative diseases, particularly in HD and PD.

BackgroundMounting evidence supports a significant role of inflammation in Parkinson's disease (PD) pathophysiology, with several inflammatory pathways being suggested as playing a role in the dopaminergic degeneration seen in humans and animal models of the disease. These include tumor necrosis factor, prostaglandins and oxidative-related stress components. However, the role of innate immunity has not been established in PD.MethodsBased on the fact that the myeloid differentiation primary response gene (88) (MyD88) is the most common adaptor protein implicated in toll-like receptor (TLR) signaling, critical in the innate immune response, we undertook a study to investigate the potential contribution of this specific pathway to MPTP-induced brain dopaminergic degeneration using MyD88 knock out mice (MyD88-/-), following our observations that the MyD88-dependent pathway was critical for MPTP dopaminergic toxicity in the enteric nervous system. Post-mortem analyses assessing nigrostriatal dopaminergic degeneration and inflammation were performed using HPLC, western blots, autoradiography and immunofluorescence.ResultsOur results demonstrate that MyD88-/- mice are as vulnerable to MPTP-induced dopamine and DOPAC striatal depletion as wild type mice. Furthermore, MyD88-/- mice show similar striatal dopamine transporter and tyrosine hydroxylase loss, as well as dopaminergic cell loss in the substantia nigra pars compacta in response to MPTP. To evaluate the extent of the inflammatory response created by the MPTP regimen utilized, we further performed bioluminescence imaging using TLR2-luc/gfp transgenic mice and microglial density analysis, which revealed a modest brain microglial response following MPTP. This was accompanied by a significant astrocytic reaction in the striatum, which was of similar magnitude both in wild type and MyD88-/- mice.ConclusionsOur results suggest that subacute MPTP-induced dopaminergic degeneration observed in the central nervous system is MyD88-independent, in contrast to our recent observations that this pathway, in the same cohort of animals, is critical in the loss of dopaminergic neurons in the enteric nervous system.