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. 2020 Apr 27;6(4):e03844.
doi: 10.1016/j.heliyon.2020.e03844. eCollection 2020 Apr.

Using the NGF/IL-6 ratio as a reliable criterion to show the beneficial effects of progesterone after experimental diffuse brain injury

Shirazpour Sara  1 , Khaksari Mohammad  2 , Shahrokhi Nader  3 , Iranpour Maryam  4 , Shahryari Marzieh  5 , Jafari Elham  4 , Salmani Neda  6
Affiliations

Using the NGF/IL-6 ratio as a reliable criterion to show the beneficial effects of progesterone after experimental diffuse brain injury

Shirazpour Sara et al. Heliyon. .

Abstract

Acute progesterone injection has been shown to reduce brain edema following traumatic brain injury (TBI) due to its neuroprotective effect. We investigated the effects of sustained release of progesterone through implantation of subcutaneous capsules on rat's brain edema and alteration of cerebrospinal fluid (CSF), and serum ratio of NGF/IL-6 after TBI. This experiment was performed on ovariectomized (OVX) rats and the brain injury was induced by Marmarou's method. A high and a low dose of progesterone (HP and LP) was injected intraperitoneally two h after the brain injury. In addition, in the capsule progesterone-treated group (CP), the intervention was implemented 6 h after the brain injury. Brain edema, NGF and IL-6 biomarkers in serum and cerebrospinal fluid (CSF) were measured 48 h after the TBI in injection groups and one week after the TBI in the CP group. No significant difference was found in the two groups or in the admonition methods. After TBI, the NGF level increased and IL-6 level decreased by injection of both doses, as well as by taking the capsule. Ratio of NGF/IL-6 in CSF increased significantly by all forms of progesterone administration. The increase in the level of NGF and IL-6 after TBI was higher in CSF than in serum. These results indicated that effects of progesterone in capsule form were better than the injection form. Progesterone probably works by increasing NGF and reducing IL-6. Future studies should investigate the ratio of these biomarkers as a variable to determine the neuroprotective effects of another drug.

Keywords: Brain edema; Endocrinology; Health sciences; IL-6; NGF/IL-6; Nervous system; Neuroscience; Physiology; Progesterone; Reproductive system; Traumatic brain injury.

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Figures

Figure 1
Figure 1
(a) The effect of progesterone administration at 2 h after TBI on brain water content (%) in OVX rats (n = 7). ∗∗∗P < 0.001, vs. Sh. ###P < 0.001, vs. Veh. (b) The effect of capsule form of progesterone on brain water content (%) in OVX rats (n = 7). ++P < 0.01, vs. Cveh (c). Changes in percentage of water content after TBI groups compared to vehicle group in rats treated with progesterone (n = 7). No significant difference was observed between LP, HP or CP groups. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 2
Figure 2
(a) The effect of progesterone administration at 2 h after TBI on CSF levels of NGF (ng/L) in OVX rats (n = 7). ∗∗∗P < 0.001, vs. Sh. (b) The effect of capsule form of progesterone on CSF levels of NGF (ng/L) in OVX rats (n = 7). + P < 0.05, vs. Cveh. (c) Changes in percentage of CSF of NGF after TBI compared with vehicle in rats treated with progesterone (n = 7). &&P < 0.01, vs.LP. & P < 0.05, vs. HP. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 3
Figure 3
(a) The effect of progesterone administration at 2 h after TBI on CSF levels of IL-6 (ng/L) in OVX rats (n = 7). ∗∗∗P < 0.001, vs. Sh.∗∗P < 0.01, vs. Sh. ##p < 0.01, vs. Veh. (b) The effect of capsule form of progesterone on IL-6 levels of IL-6 (ng/L) in OVX rats (n = 7). ++, P < 0.01.vs Cveh. (c) Changes in percentage of CSF of IL-6 after TBI compared with vehicle in rats treated with progesterone (n = 7). No significant different between LP, HP or CP groups. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 4
Figure 4
(a) The effect of progesterone administration at 2 h after TBI on CSF ratio of NGF/IL-6 in OVX rats (n = 7). #P < 0.05, vs. Veh. ###P < 0.001, vs. Veh. (b) The effect of capsule form of progesterone on CSF ratio of NGF/IL-6 in OVX rats (n = 7). +++ P < 0.001, vs. Cveh. (c) Changes in percentage of CSF ratio of NGF/IL-6 after TBI compared with vehicle in rats treated with progesterone (n = 7). && P < 0.01, vs. LP and HP. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 5
Figure 5
(a) The effect of progesterone administration at 2 h after TBI on serum levels of NGF (ng/L) in OVX rats (n = 7). ∗∗P < 0.01, vs. sh. (b) The effect of capsule form of progesterone on CSF levels of NGF (ng/L) in OVX rats (n = 7). No significant difference between TBI, CP or Cveh groups. (c) Changes in percentage of serum of NGF after TBI compared with vehicle in rats treated with progesterone (n = 7). No significant difference between LP, HP or CP groups. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 6
Figure 6
(a) The effect of progesterone administration at 2 h after TBI on serum levels of IL-6 (ng/L) in OVX rats (n = 7). ∗P < 0.05, vs. Sh.#P < 0.05, vs. Veh. ##P < 001, vs Veh. (b) The effect of capsule form of progesterone on CSF levels of IL-6 (ng/L) in OVX rats (n = 7). +++P < 0.001, vs Cveh. (c) Changes in percentage of serum of IL-6 after TBI compared with vehicle in rats treated with progesterone (n = 7). && P < 0.01, vs LP group. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 7
Figure 7
(a) The effect of progesterone administration at 2 h after TBI on serum ratio of NGF/IL-6 in OVX rats (n = 7). ##P < 0.01, vs. Veh. (b) The effect of capsule form of progesterone on serum ratio of NGF/IL-6 in OVX rats (n = 7). +++P < 0.001, vs. Cveh. (c) Changes in percentage of serum ratio of NGF/IL-6 after TBI compared with vehicle in rats treated with progesterone (n = 7). & P < 0.05, vs. LP. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP, progesterone capsule; Cveh, capsule vehicle.
Figure 8
Figure 8
Changes in CSF and serum concentration of NGF and IL-6 in different groups following diffuse traumatic brain injury (n = 7).(a) ∗∗∗ P < 0.001 and ∗∗P < 0.01 vs serum. (b) ###P < 0.001, ##P < 0.01, and #P < 0.05 vs serum. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP,progesterone capsule; Cveh, capsule vehicle.
Figure 9
Figure 9
Changes in VCS at different times in treated and non-treated rats (n = 7). ∗∗∗P < 0.001 immediately after TBI and at 1 h and4 h after TBI for sham group vs. TBI and Veh groups. #, P < 0.05 at 4 h after TBI for HP group vs. Veh group.
Figure 10
Figure 10
Changes VCS at different times in treated and non-treated rats (n = 7). No significant different between Cp and Cveh groups all the times.
Figure 11
Figure 11
Changes in percentage of VCS at 4 h after TBI with vehicle in treated rats (n = 7). && P < 0.05 HP group vs. and CP groups. Sh, sham; Veh, vehicle; LP, low progesterone; HP, high progesterone; CP,progesterone capsules; Cveh, capsule vehicle.
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