1. Medicine
  2. Neuroscience

Acute ampakines increase voiding function and coordination in a rat model of SCI

  1. Sabhya Rana
  2. Firoj Alom
  3. Robert C Martinez
  4. David D Fuller
  5. Aaron D Mickle  Is a corresponding author
  1. Department of Physical Therapy, University of Florida, United States
  2. McKnight Brain Institute, University of Florida, United States
  3. Breathing Research and Therapeutics Center, United States
  4. Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, United States
  5. Department of Veterinary and Animal Sciences, University of Rajshahi, Bangladesh
  6. J. Crayton Pruitt Family Department of Biomedical Engineering, College of Engineering, University of Florida, United States
https://doi.org/10.7554/eLife.89767.3
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  1. Sabhya Rana
  2. Firoj Alom
  3. Robert C Martinez
  4. David D Fuller
  5. Aaron D Mickle
(2024)
Acute ampakines increase voiding function and coordination in a rat model of SCI
eLife 12:RP89767.
https://doi.org/10.7554/eLife.89767.3
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6 figures, 1 table and 3 additional files

Figures

Figure 1
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Histological assessment of T9 contusion (T9Ct) injury epicenter.

Serial, transverse sections (20 μm thickness) spanning ~1 cm around the lesion epicenter (T9–T10) were stained with cresyl violet in order to identify the extent of injury. A representative image from a spinal intact (left) and T9 contused (right) spinal cord. Scale bar, 300 μm.

Figure 2
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Impact of T9 contusion on cystometric bladder function and external urethral sphincter (EUS) electromyography (EMG) activity.

(A) Example bladder pressure and EUS EMG trace of coordinated voiding in spinal intact animals (left column) and rats with spinal cord injury (SCI), 5 d following SCI (right column). Expanded traces show EUS EMG activity. Note different y-scales in expanded trace used for clarity. (B–E) Summary of the impact of T9 contusion injury on various cystometric outcomes. Baseline pressure was reduced in the SCI group compared to spinal intact animals. Injured rats had significantly higher threshold pressures, voided volume, and intercontraction intervals. (B) Baseline pressure (cmH2O); (C) threshold pressure (cmH2O); (D) voided volume (μl); (E) intercontraction interval (s). (F–I) Summary of the impact of T9 contusion injury on EUS EMG activity. Injured rats had a significantly higher duration, area under the curve, and RMSpeak EMG. (F) Threshold (cmH2O); (G) duration (s); (H) area under the curve (arbitrary unit, a.u.); (I) RMSpeak EMG (a.u.). *p<0.05. Data are presented as bar plots, with all individual data points corresponding to individual animal means. Group means are represented with a diamond, with error bars depicting ±SE.

Figure 3
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Impact of ampakine treatment on cystometric bladder function.

(A) Example trace of bladder cystometry in spinal intact animals (left column) and rats with spinal cord injury (SCI) 5 d following SCI (right column) and following 2-hydroxypropyl-beta-cyclodextrin (HPCD) or ampakine infusion (5, 10, 15 mg/kg). (B–E) Summary of the impact of ampakine treatment on cystometric outcomes in spinal intact (n = 8) rats and rats with SCI (n = 7). Ampakine treatment significantly reduced the intercontraction interval, voided volume, and threshold pressure in injured rats. HPCD did not alter cystometry parameters compared to baseline. Ampakine treatment caused a decrease in threshold and peak pressure but did not affect intercontraction interval or voided volume in intact rats. (B) Intercontraction interval (s); (C) peak pressure (cmH2O); (D) voided volume (μl); (E) threshold pressure (cmH2O). Data are presented as line plots, with all individual data points corresponding to an individual animal means. Group means are represented with a diamond, with error bars depicting ±SE.

Figure 4
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Impact of ampakine treatment on external urethral sphincter (EUS) electromyography (EMG) activity.

(A, B) Example bladder pressure trace, raw EUS EMG trace (blue), and RMS EUS EMG (orange) activity during spontaneous voiding in spinal intact animals and rats with spinal cord injury (SCI) 5 d following SCI following 2-hydroxypropyl-beta-cyclodextrin (HPCD) or ampakine infusion (5, 10, 15 mg/kg). Note the re-emergence of coordinated EUS EMG activity following 15 mg/kg ampakine treatment in injured rats (black arrow). (C–F) Summary of the impact of ampakine treatment on EUS EMG activity in spinal intact rats (n = 8) and rats with SCI (n = 7). Ampakine treatment reduced the threshold pressure in spinal intact rats and rats with SCI. HPCD had no impact on any outcomes. (C) Duration (s); (D) threshold (cmH2O; defined as the bladder pressure at which EUS EMG burst was evoked [intersection of red dotted lines]); (E) area under the curve (arbitrary unit, a.u.); (F) RMSpeak EMG (a.u.). Data are presented as line plots, with all individual data points corresponding to individual animal means. Group means are represented by a diamond, with error bars depicting ±SE.

Figure 5
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Ampakine rescue coordinated voiding in non-voiding rats following spinal cord injury (SCI).

(A) Example bladder pressure and external urethral sphincter (EUS) electromyography (EMG) trace of non-coordinated voiding 5 d following SCI (baseline). Black arrows indicate manual expression/emptying of the bladder. The second trace (post-ampakine) indicates the same rat following 10 mg/kg CX1739 with voiding re-established. Expanded EUS EMG trace in the middle panels shows the lack of coordinated bursting during baseline recording of rats with SCI (i). Following ampakine treatment, coordinated EUS bursting is restored (gray arrows; ii). (B–F) Summary of the impact of 10 mg/kg ampakine treatment on cystometry and EUS EMG outcomes in rats with SCI displaying non-coordinated voiding (n = 3). Ampakine treatment reduced non-voiding and partial voiding contractions in all three rats and established coordinated voiding. No rat exhibited coordinated EUS bursting during the voiding phase at baseline. Ampakine treatment re-established coordinated EUS bursting in all three rats. (B) Non-voiding contractions; (C) complete voiding contractions; (D) non-complete voiding contractions; (E) RMSpeak EMG; (F) EUS EMG bursting events. Data are presented as individual data points corresponding to individual animal means.

Figure 6
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Experimental setup and design.

(A) Schematic of experimental urodynamic recordings in anesthetized rats. Volume of voided urine was also collected. (B) Experimental timeline of studies. Animals received a unilateral T9 contusion, and urodynamic recordings were conducted at 5 d post contusion. During the recording, a baseline was established for urodynamic output. Animals received vehicle 2-hydroxypropyl-beta-cyclodextrin (HPCD), and consecutive doses of ampakines CX1739 at doses of 5, 10, and 15 mg/kg. Each drug dose was spaced apart by 45 min.

© 2024, BioRender Inc. Figure 6 was created using BioRender (agreement # GZ26GBTL9J), and is published under a CC BY-NC-ND license. Further reproductions must adhere to the terms of this license.

Tables

Table 1
Statistical post hoc comparisons for cystometric outcomes with significant treatment and group interactions in spontaneously voiding intact (n = 8) rats and rats with SCI (n = 7) following ampakine treatment.
GroupTreatmentThresholdIntercontraction intervalVoided volume
IntactBaselineA, BDC
HPCDA, B, CDC
5 mg/kgB, C, DDC
10 mg/kgDDC
15 mg/kgDDC
SCIBaselineAA, BA
HPCDAAA
5 mg/kgB, C, DB, CB
10 mg/kgC, DC, DB, C
15 mg/kgDC, DB, C

  1. Levels not connected by the same letter are significantly different.

  2. HPCD, 2-hydroxypropyl-beta-cyclodextrin; SCI, spinal cord injury.

Additional files

Supplementary file 1

Mean data of cystometry measures at 5 d post-injury following HPCD or ampakine CX1739 treatment.

https://cdn.elifesciences.org/articles/89767/elife-89767-supp1-v1.docx
Supplementary file 2

Mean data of EUS EMG activity at 5 d post-injury following HPCD or ampakine CX1739 treatment.

https://cdn.elifesciences.org/articles/89767/elife-89767-supp2-v1.docx
MDAR checklist
https://cdn.elifesciences.org/articles/89767/elife-89767-mdarchecklist1-v1.docx

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  1. Sabhya Rana
  2. Firoj Alom
  3. Robert C Martinez
  4. David D Fuller
  5. Aaron D Mickle
(2024)
Acute ampakines increase voiding function and coordination in a rat model of SCI
eLife 12:RP89767.
https://doi.org/10.7554/eLife.89767.3