Systolic and diastolic blood pressure measurements during 6-OHDA administration.

<p>Blood pressure results from a representative animal (RH2318). A, Both pressures increase immediately after each 6-OHDA dosing (arrows). B, Change in systolic and diastolic blood pressure from peak of pressure following 6-OHDA until levels normalized at which time the next injection of 6-OHDA was administered. The amount of time to normalize paralleled the change in blood pressure. At the accumulated dose of 2.0 mg/kg, this animal required 61 minutes to regulate blood pressure. bp, blood pressure.</p

Echocardiogram measurements at baseline, 10 and 14 weeks after 6-OHDA for each animal.

<p>FS is calculated as [(LVD_d – LVD_s)/LVD_d]×100. Three animals experienced large decreases in FS compared to baseline, but there was no significant change in left ventricle diameter or in anterior and posterior wall thickness. This suggests that the increased luminal dimensions of the left ventricle were not due to the loss of cardiac muscle. AWd, anterior wall thickness in diastole. AWs, anterior wall thickness in systole. PWd, posterior wall thickness in diastole. PWs, posterior wall thickness in systole. LVD_d, left ventricle diameter in diastole. LVD_s, left ventricle diameter in systole. FS, fractional shortening.</p

Experimental timeline.

<p>All procedures were performed in 5 adult rhesus monkeys following a within-subject experimental design. MHED PET scans, plasma catecholamines, troponin I and ECGs (*) were performed at baseline and 1, 4, 10 and 14 weeks after 6-OHDA. Echocardiograms (Echo) were obtained at baseline and 10 and 14 weeks after 6-OHDA. Clinical rating (CR) was performed at baseline and 4, 10 and 14 weeks following toxin administration. Food consumption and feces were monitored daily and body weight was measured weekly throughout the course of the study (shading). Animals were euthanized 14 weeks following 6-OHDA administration.</p

Distribution volume maps before and after systemic 6-OHDA dosing.

<p>Maps express regional capacity of the tissue for MHED uptake relative to whole blood, thus providing a measure of the density of nerve terminals. Each individual map consists of 8 sectors and 7 rings (apex of the heart at the center, base of the LV at the edge), totaling to 56 blocks of data per timepoint. MHED uptake significantly decreased at each timepoint after 6-OHDA compared to baseline (<i>P</i><0.001). Scales (mL whole blood/g tissue) are similar between animals and identical across time points for each individual. The compass rose indicates regions: A, anterior; S, septal; I, inferior; L, lateral.</p

6-OHDA dosing scheme (mg/kg) for each individual animal.

<p>The rhesus monkeys received 7–9 injections of 6-OHDA solution in one session, accumulating to a total final dose of 50 mg/kg. Dosing and timeline of injections varied based on the individual reaction to 6-OHDA. The normalization (return to baseline measures) of vital signs, ECG, heart rate, and blood pressure was used to define when the next dose could be given.</p

Quantitative analysis of MHED PET.

<p>A, Group mean global MHED % retention deficit comparing 1, 4, 10, and 14 weeks after toxin to baseline. B, Group mean regional MHED uptake comparing anterior, inferior, septal, and lateral regions of the left ventricle at baseline and at 1, 4, 10, and 14 weeks after toxin. *<i>P</i><0.05, ** <i>P</i><0.01, *** <i>P</i><0.001.</p

Circulating plasma catecholamine levels (pg/mL) at baseline (0) and at 1, 4, 10, and 14 weeks after 6-OHDA in three animals.

<p>The values in parentheses are the natural logarithms of the concentration values and used to graph correlations in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0035371#pone-0035371-g005" target="_blank">Figure 5</a>. For statistical analysis, non-detectable levels (nd) levels were considered as the lowest detection level with 1.5 pg/mL for norepinephrine and 3.0 pg/mL for epinephrine. Post hoc analysis with Bonferroni multiple comparisons detected significance at all timepoints compared to baseline for norepinephrine and DOPAC (*<i>P</i><0.05, ** <i>P</i><0.01).</p

Weekly animal weights (kg) and average group % weight loss before and after 6-OHDA dosing.

<p>A significant loss of weight was found starting at four weeks post 6-OHDA challenge and persisting throughout the study.</p>*<p><i>P</i><0.05,</p>**<p><i>P</i><0.01.</p

Electrocardiogram (ECG) measurements at baseline, 1, 4, 10 and 14 weeks after 6-OHDA for each animal.

<p>QTc was calculated using the Bazett's formula as QT interval/sqrt (RR interval), where the RR interval was calculated 60/HR. ΔQTc was calculated as QTc of each time point minus baseline. No significant differences were found in PR, QRS and QTc intervals obtained in anesthetized animals. HR, heart rate. QTc, corrected QT interval.</p