PMC:4627622 / 12501-19832
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4627622","sourcedb":"PMC","sourceid":"4627622","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4627622","text":"Results\n\nPhysiological data\nThe physiological parameters were examined after 2, 24 and 48 h for CFA, and at 2 and 24 h for IS (Table 1). No significant differences regarding measured physiological data (Na+, K+, pH, pCO2, pO2 and MAP) were observed between the groups.\nTable 1 Physiological parameters in animals where Ki for 51Cr-EDTA was determined. Hematocrit in animals treated with CFA was lower than in the vehicle group at 24 h following application to the dura. No other differences regarding measured physiological data were observed between the groups\nVehicle (n = 6) CFA 2 h (n = 6) CFA 24 h (n = 5) CFA 48 h (n = 5) IS 2 h (n = 6) IS 24 h (n = 4)\nMAP (mmHg) 98 ± 7 88 ± 3 87 ± 6 105 ± 7 85 ± 5 104 ± 9\nHct (%) 50 ± 2 46 ± 3 38 ± 2* 42 ± 1 46 ± 2 42 ± 2\npCO2 (kPa) 4.6 ± 0.1 4.6 ± 0.1 4.7 ± 0.2 4.5 ± 0.1 4.6 ± 0.1 4.8 ± 0.2\npO2 (kPa) 11.5 ± 0.1 11.6 ± 0.1 11.0 ± 0.2 12.7 ± 0.5 11.4 ± 0.3 11.4 ± 0.5\nNa+ (mmol) 136.3 ± 0.6 138.0 ± 1.6 138.6 ± 1.0 137.0 ± 0.5 137.0 ± 0.5 136.5 ± 0.9\nK+(mmol) 4.82 ± 0.39 4.65 ± 0.39 4.36 ± 0.13 4.40 ± 0.13 4.57 ± 0.14 4.55 ± 0.22\npH 7.50 ± 0.02 7.45 ± 0.02 7.46 ± 0.02 7.46 ± 0.01 7.48 ± 0.01 7.48 ± 0.01\nDifferences in plasma volumes in tissue was found following application of both CFA and IS compared to vehicle (*p \u003c 0.05)\n\nPhoto microscopy\nWe were interested in observing whether the addition of IS or CFA in our model had any direct effect at the place of addition on the dura mater, using photo microscopy. It is worth pointing out that removal of the bone for the direct application on the dura, reduces the possible changes that can be observed in meningeal vasculature (see discussion). 15 min after the addition of IS (Fig. 1a/b) and CFA (Fig. 1c/d) we did not observe any changes in the meningeal vasculature (white arrows). However, there appears to be an weak increase in brain blood vessel diameter (black arrows), particularly after CFA.\nFig. 1 Dural effect of IS and CFA. Addition of IS and CFA on the dura mater. The control picture was taken at time 0 for IS (a) and CFA (c). The effect of 15 min. stimulation can been observed after IS (b) and CFA (d). Representative pictures. White arrows meningeal vasculature, black arrows brain vasculature\n\nPermeability-surface area product for [51Cr]- EDTA\nIn order to study the permeability surface area product (PS), [51Cr]-EDTA was injected as a bolus dose (370 bq) followed by continuous infusion 0.33 ml/h (3.7 MBq/ml). To correct for tissue plasma volume, a bolus dose of [125I]-albumin was injected 3 min before the experiment was terminated and tissue collected. The plasma content, which is used to correct the [51Cr]-EDTA data (Table 2), was significantly higher 2 h after CFA treatment in PAG and cerebellum. 48 h after CFA treatment the plasma content was significantly higher in the spinal trigeminal nucleus. For IS a small increase was observed in the cerebellum at 24 h and with a minor change in the TNC. This increased plasma content suggests a larger blood volume that was increased due to the inflammation.\nTable 2 Plasma volume in tissue in analyzed brain structures. Plasma volume in analyzed structures following application of CFA or IS to the dura was compared to plasma volume in analyzed structure following application of vehicle\nControl CFA 2 h CFA 24 h CFA 48 h IS 2 h IS 24 h\nCortex (μL/mg) 7.3 + 0.6 12.2 ± 2.5 12.6 ± 0.8* 14.6 + 3.0* 11.3 ± 0.7* 11.0 ± 2.0\nPAG (μL/mg) 6.0 ± 0.6 15.3 ± 3.2* 12.8 ± 1.4* 8.8 ± 1.5 13.8 ± 2.9 11.8 ± 2.3\nCerebellum (μL/mg) 9.5 ± 0.4 14.2 ± 0.8* 12.8 ± 0.5 29.4 ± 6.2 * 13.8 ± 1.7 16.3 ± 1.3*\nL Spinal Trigeminal nucleus (μL/mg) 10.3 ± 1.7 14.3 ± 2.3 21.2 ± 2.1* 44.0 ± 14.4* 12.5 ± 3.5* 27.0 ± 8.9\nR Spinal Trigeminal nucleus (μL/mg) 12.8 ± 2.6 13.7 ± 1.6 19.4 ± 1.8 23.6 ± 3.4* 16.0 ± 1.8 28.0 ± 11.0\nL Trigeminal Ganglion (μL/mg) 52.3 ± 4.3 53.3 ± 12.5 48.0 ± 8.0 25.8 ± 3.1 40.5 ± 13.4 59.3 ± 10.3\nR Trigeminal Ganglion (μL/min/g) 54.5 ± 5.7 51.7 ± 10.4 68.2 ± 13.9 22.0 ± 2.6 56.7 ± 15.5 83.8 ± 27.4\nDifferences in plasma volumes in tissue was found following application of both CFA and IS compared to vehicle (*p \u003c 0.05)\nWe investigated the left and right TG and TNC individually. IS and CFA was only added on the left parietal bone, and we were interested in observing a direct link between the dural application and the corresponding TG and TNC structures. The control data where saline has been applied to the dura mater show that the TG is \u003e30 times more permeable than cerebellum/cortex and \u003e200 times than the PAG (Fig. 2a). In addition, the permeability of the TG was also \u003e30 times higher than the spinal TNC. This clearly illustrates that the TG has much higher permeability than the CNS and is also in agreement with the 3 % of triptans/gepants that can reach the CNS [5, 9–11] as the cortex/cerebellum has a permeability that is ~3 % of TG. In addition we also show that Evans blue, that cannot pass the BBB (Evans blue binds to serum albumin, creating a large molecule that can be visualized), colours the TG but not the brain (Fig. 2b). The dura mater was likewise “blue” after the administration of EBA (Fig. 2c). Due to the operation and manipulations we did not quantify the dura mater permeability.\nFig. 2 Comparison of the PS for the different structures analysed. a The PS of the TG is much larger than that of the other structures investigated. b Rat brain and TG after perfusion of Evans blue shows that the TG is permeable whereas the brain is not. c The dura mater is permeable to Evans blue\nWe further characterized the changes in permeability following the addition of CFA and IS onto the dura. There were no significant increases in the permeability of the cortex, cerebellum or PAG following either of the inflammation triggers (Fig. 3) compared to vehicle, suggesting that permeability does not change in the inflammatory models. A small permeability increase in the spinal TNC was observed after 24 h of CFA, although the change is nearly negligible as it after CFA still is \u003e10 times less permeable than the TG (Fig. 4). We observed a small decrease in the left TG with the same tendency in the right TG, which could be due to the increased ganglion activation. We did not observe any significant changes in any of the structures examined after either 2 or 24 h after the addition of IS.\nFig. 3 PS in the cortex cerebellum and PAG after treatment with CFA or IS. The figure shows PS for 51Cr-EDTA in the cortex (a), cerebellum (b) and periaquaductal grey (c). PS for treatment following application of CFA or IS to the dura was compared to PS following application of vehicle to the dura. *p ≤0.05\nFig. 4 PS in the TG and spinal trigeminal nucleus after treatment with CFA or IS. The figure shows PS for 51Cr-EDTA in the left TNC (a), right TNC (b), left TG (c), and right TG (d). PS for treatment following application of CFA or IS to the dura was compared to PS following application of vehicle to the dura. *p ≤0.05\nTo ensure that there was no oedema in the brain, we measured the brain water content (Additional file 1: Figure S1). There were no significant changes in water content in the CNS. Only the left TG showed an increase of 10 % at 48 h after CFA application onto the dura. This also supports the permeability studies as a lowered permeability in the BBB, most likely would have led to increased water content.","divisions":[{"label":"title","span":{"begin":0,"end":7}},{"label":"sec","span":{"begin":9,"end":1273}},{"label":"title","span":{"begin":9,"end":27}},{"label":"p","span":{"begin":28,"end":1273}},{"label":"table-wrap","span":{"begin":269,"end":1273}},{"label":"label","span":{"begin":269,"end":276}},{"label":"caption","span":{"begin":277,"end":561}},{"label":"p","span":{"begin":277,"end":561}},{"label":"table","span":{"begin":562,"end":1150}},{"label":"tr","span":{"begin":562,"end":658}},{"label":"th","span":{"begin":562,"end":577}},{"label":"th","span":{"begin":578,"end":593}},{"label":"th","span":{"begin":594,"end":610}},{"label":"th","span":{"begin":611,"end":627}},{"label":"th","span":{"begin":628,"end":642}},{"label":"th","span":{"begin":643,"end":658}},{"label":"tr","span":{"begin":659,"end":713}},{"label":"td","span":{"begin":659,"end":669}},{"label":"td","span":{"begin":670,"end":676}},{"label":"td","span":{"begin":677,"end":683}},{"label":"td","span":{"begin":684,"end":690}},{"label":"td","span":{"begin":691,"end":698}},{"label":"td","span":{"begin":699,"end":705}},{"label":"td","span":{"begin":706,"end":713}},{"label":"tr","span":{"begin":714,"end":764}},{"label":"td","span":{"begin":714,"end":721}},{"label":"td","span":{"begin":722,"end":728}},{"label":"td","span":{"begin":729,"end":735}},{"label":"td","span":{"begin":736,"end":743}},{"label":"td","span":{"begin":744,"end":750}},{"label":"td","span":{"begin":751,"end":757}},{"label":"td","span":{"begin":758,"end":764}},{"label":"tr","span":{"begin":765,"end":835}},{"label":"td","span":{"begin":765,"end":775}},{"label":"td","span":{"begin":776,"end":785}},{"label":"td","span":{"begin":786,"end":795}},{"label":"td","span":{"begin":796,"end":805}},{"label":"td","span":{"begin":806,"end":815}},{"label":"td","span":{"begin":816,"end":825}},{"label":"td","span":{"begin":826,"end":835}},{"label":"tr","span":{"begin":836,"end":911}},{"label":"td","span":{"begin":836,"end":845}},{"label":"td","span":{"begin":846,"end":856}},{"label":"td","span":{"begin":857,"end":867}},{"label":"td","span":{"begin":868,"end":878}},{"label":"td","span":{"begin":879,"end":889}},{"label":"td","span":{"begin":890,"end":900}},{"label":"td","span":{"begin":901,"end":911}},{"label":"tr","span":{"begin":912,"end":994}},{"label":"td","span":{"begin":912,"end":922}},{"label":"td","span":{"begin":923,"end":934}},{"label":"td","span":{"begin":935,"end":946}},{"label":"td","span":{"begin":947,"end":958}},{"label":"td","span":{"begin":959,"end":970}},{"label":"td","span":{"begin":971,"end":982}},{"label":"td","span":{"begin":983,"end":994}},{"label":"tr","span":{"begin":995,"end":1075}},{"label":"td","span":{"begin":995,"end":1003}},{"label":"td","span":{"begin":1004,"end":1015}},{"label":"td","span":{"begin":1016,"end":1027}},{"label":"td","span":{"begin":1028,"end":1039}},{"label":"td","span":{"begin":1040,"end":1051}},{"label":"td","span":{"begin":1052,"end":1063}},{"label":"td","span":{"begin":1064,"end":1075}},{"label":"tr","span":{"begin":1076,"end":1150}},{"label":"td","span":{"begin":1076,"end":1078}},{"label":"td","span":{"begin":1079,"end":1090}},{"label":"td","span":{"begin":1091,"end":1102}},{"label":"td","span":{"begin":1103,"end":1114}},{"label":"td","span":{"begin":1115,"end":1126}},{"label":"td","span":{"begin":1127,"end":1138}},{"label":"td","span":{"begin":1139,"end":1150}},{"label":"table-wrap-foot","span":{"begin":1151,"end":1273}},{"label":"p","span":{"begin":1151,"end":1273}},{"label":"sec","span":{"begin":1275,"end":2211}},{"label":"title","span":{"begin":1275,"end":1291}},{"label":"p","span":{"begin":1292,"end":2211}},{"label":"figure","span":{"begin":1901,"end":2211}},{"label":"label","span":{"begin":1901,"end":1907}},{"label":"caption","span":{"begin":1908,"end":2211}},{"label":"p","span":{"begin":1908,"end":2211}},{"label":"title","span":{"begin":2213,"end":2263}},{"label":"p","span":{"begin":2264,"end":4097}},{"label":"table-wrap","span":{"begin":3034,"end":4097}},{"label":"label","span":{"begin":3034,"end":3041}},{"label":"caption","span":{"begin":3042,"end":3264}},{"label":"p","span":{"begin":3042,"end":3264}},{"label":"table","span":{"begin":3265,"end":3974}},{"label":"tr","span":{"begin":3265,"end":3313}},{"label":"th","span":{"begin":3265,"end":3272}},{"label":"th","span":{"begin":3273,"end":3280}},{"label":"th","span":{"begin":3281,"end":3289}},{"label":"th","span":{"begin":3290,"end":3298}},{"label":"th","span":{"begin":3299,"end":3305}},{"label":"th","span":{"begin":3306,"end":3313}},{"label":"tr","span":{"begin":3314,"end":3396}},{"label":"td","span":{"begin":3314,"end":3328}},{"label":"td","span":{"begin":3329,"end":3338}},{"label":"td","span":{"begin":3339,"end":3349}},{"label":"td","span":{"begin":3350,"end":3361}},{"label":"td","span":{"begin":3362,"end":3373}},{"label":"td","span":{"begin":3374,"end":3385}},{"label":"td","span":{"begin":3386,"end":3396}},{"label":"tr","span":{"begin":3397,"end":3474}},{"label":"td","span":{"begin":3397,"end":3408}},{"label":"td","span":{"begin":3409,"end":3418}},{"label":"td","span":{"begin":3419,"end":3430}},{"label":"td","span":{"begin":3431,"end":3442}},{"label":"td","span":{"begin":3443,"end":3452}},{"label":"td","span":{"begin":3453,"end":3463}},{"label":"td","span":{"begin":3464,"end":3474}},{"label":"tr","span":{"begin":3475,"end":3562}},{"label":"td","span":{"begin":3475,"end":3493}},{"label":"td","span":{"begin":3494,"end":3503}},{"label":"td","span":{"begin":3504,"end":3515}},{"label":"td","span":{"begin":3516,"end":3526}},{"label":"td","span":{"begin":3527,"end":3539}},{"label":"td","span":{"begin":3540,"end":3550}},{"label":"td","span":{"begin":3551,"end":3562}},{"label":"tr","span":{"begin":3563,"end":3668}},{"label":"td","span":{"begin":3563,"end":3598}},{"label":"td","span":{"begin":3599,"end":3609}},{"label":"td","span":{"begin":3610,"end":3620}},{"label":"td","span":{"begin":3621,"end":3632}},{"label":"td","span":{"begin":3633,"end":3645}},{"label":"td","span":{"begin":3646,"end":3657}},{"label":"td","span":{"begin":3658,"end":3668}},{"label":"tr","span":{"begin":3669,"end":3772}},{"label":"td","span":{"begin":3669,"end":3704}},{"label":"td","span":{"begin":3705,"end":3715}},{"label":"td","span":{"begin":3716,"end":3726}},{"label":"td","span":{"begin":3727,"end":3737}},{"label":"td","span":{"begin":3738,"end":3749}},{"label":"td","span":{"begin":3750,"end":3760}},{"label":"td","span":{"begin":3761,"end":3772}},{"label":"tr","span":{"begin":3773,"end":3871}},{"label":"td","span":{"begin":3773,"end":3802}},{"label":"td","span":{"begin":3803,"end":3813}},{"label":"td","span":{"begin":3814,"end":3825}},{"label":"td","span":{"begin":3826,"end":3836}},{"label":"td","span":{"begin":3837,"end":3847}},{"label":"td","span":{"begin":3848,"end":3859}},{"label":"td","span":{"begin":3860,"end":3871}},{"label":"tr","span":{"begin":3872,"end":3974}},{"label":"td","span":{"begin":3872,"end":3904}},{"label":"td","span":{"begin":3905,"end":3915}},{"label":"td","span":{"begin":3916,"end":3927}},{"label":"td","span":{"begin":3928,"end":3939}},{"label":"td","span":{"begin":3940,"end":3950}},{"label":"td","span":{"begin":3951,"end":3962}},{"label":"td","span":{"begin":3963,"end":3974}},{"label":"table-wrap-foot","span":{"begin":3975,"end":4097}},{"label":"p","span":{"begin":3975,"end":4097}},{"label":"p","span":{"begin":4098,"end":5491}},{"label":"figure","span":{"begin":5193,"end":5491}},{"label":"label","span":{"begin":5193,"end":5199}},{"label":"caption","span":{"begin":5200,"end":5491}},{"label":"p","span":{"begin":5200,"end":5491}},{"label":"p","span":{"begin":5492,"end":6925}},{"label":"figure","span":{"begin":6295,"end":6604}},{"label":"label","span":{"begin":6295,"end":6301}},{"label":"caption","span":{"begin":6302,"end":6604}},{"label":"p","span":{"begin":6302,"end":6604}},{"label":"figure","span":{"begin":6605,"end":6925}},{"label":"label","span":{"begin":6605,"end":6611}},{"label":"caption","span":{"begin":6612,"end":6925}},{"label":"p","span":{"begin":6612,"end":6925}}],"tracks":[{"project":"TEST0","denotations":[{"id":"26512021-161-166-1479095","span":{"begin":4756,"end":4757},"obj":"[\"24638916\"]"},{"id":"26512021-164-169-1479096","span":{"begin":4759,"end":4760},"obj":"[\"20430315\", \"23975906\"]"}],"attributes":[{"subj":"26512021-161-166-1479095","pred":"source","obj":"TEST0"},{"subj":"26512021-164-169-1479096","pred":"source","obj":"TEST0"}]},{"project":"2_test","denotations":[{"id":"26512021-24638916-60534737","span":{"begin":4756,"end":4757},"obj":"24638916"},{"id":"26512021-20430315-60534738","span":{"begin":4759,"end":4760},"obj":"20430315"},{"id":"26512021-23975906-60534738","span":{"begin":4759,"end":4760},"obj":"23975906"}],"attributes":[{"subj":"26512021-24638916-60534737","pred":"source","obj":"2_test"},{"subj":"26512021-20430315-60534738","pred":"source","obj":"2_test"},{"subj":"26512021-23975906-60534738","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"TEST0","color":"#ec93e8","default":true},{"id":"2_test","color":"#93ecd6"}]}]}}