Table 1.
List of preclinical studies involving drugs that target GABAergic neurotransmission in TBI.
| Drug | Injury model and animal groups | Drug administration timeline | Effect on histological outcome and functional recovery |
|---|---|---|---|
| Propofol (19) | CCI Sprague-Dawley rats n = 9 for each experimental drug group (diazepam, fentanyl, morphine, isoflurane, ketamine, pentobarbital, ketamine, no anesthesia and sham) |
Drug administration for 1-h post TBI. | No effect on histological outcome (lesion volume and surviving hippocampal neurons measured at 21 days post TBI). Propofol administration affected motor function recovery (first 5 days post TBI) but had no effect on cognitive recovery (14–20 days post TBI). |
| Propofol (32) | CCI C57BL/6 mice n = 10 for each group (propofol at 6 or 24-h and vehicle or saline) |
Single bolus of propofol administration post TBI (6–24-h). | Increased lesion volume observed at 72-h post CCI in the propofol treated cohort. Propofol administration impaired recovery of locomotor function (gait analysis at 30 days post TBI). |
| Propofol (31) | CCI Sprague-Dawley rats n = 10–17 for each group. Groups tested were sham (low and high dose) and CCI (low and high dose) |
Drug administration during (for 2-h, 30 min before and 90 min after) or post TBI (for 3-h at 2-h post injury). | Propofol had no effect on the lesion size (28 days post insult). Propofol impaired recovery of neurological function at 28 days post insult in a dose-dependent manner. |
| Propofol (33) | CCI Sprague-Dawley rats n = 9–10 for each group. Groups tested were CCI (propofol high and low dose), CCI (halothane) and sham |
Drug administered post TBI for 6-h. | Propofol (at both doses) did not exert any effect on the lesion volume and eosinophilic cell count in the hippocampus (at 6-h post insult). |
| Propofol (35) | FPI Sprague-Dawley rats n = 6–8 for each group. Groups tested were FPI (propofol and isoflurane) and sham |
Continuous propofol infusion before TBI induction. | Propofol decreased the lesion volume (at 28 days post TBI induction) compared to isoflurane anesthesia. Propofol aided the recovery of cognitive function in novel object recognition task at 21 days post TBI. |
| Propofol (36) | CCI Sprague-Dawley rats TBI + drug (n = 10) TBI + no drug (n = 10) Sham + saline (n = 8) No TBI + drug (n = 10) |
Intra-peritoneal injection given at 10 min post TBI. | Propofol reduced formation of cerebral edema (estimated at 12-h post TBI). |
| Propofol (37) | CCI Sprague-Dawley rats n = 9 for each of the seven experimental groups as mentioned in the paper |
Propofol delivered at 1, 2, and 4-h post TBI through intra-peritoneal injection and followed by 2-h infusion. | Propofol reduced cell death in the peri-contusional cortex at 24-h post CCI. |
| Diazepam (19) | CCI Sprague-Dawley rats n = 9 for each experimental drug group (diazepam, fentanyl, morphine, isoflurane, ketamine, pentobarbital, ketamine, no anesthesia and sham) |
Drug administration for 1-h post TBI. | No effect on histological outcome by diazepam (lesion volume and surviving hippocampal neurons) at 21 days post TBI. Diazepam administration affected cognitive recovery assessed through MWM test at 14–20 days post TBI. |
| Diazepam (38) | CCI C57BL/6J mice TBI + drug (n = 13) TBI + vehicle (n = 13) Sham + drug (n = 14) Sham + vehicle (n = 12) |
Continuous drug infusion for 1-week post TBI through an osmotic pump. | Diazepam did not have any effect on tissue loss or number of degenerating cells at 3 days post injury. |
| Midazolam (39) | CCI C57BL/6 mice n = 9–11 for each group (TBI + saline, TBI + low dose midazolam, TBI + high dose midazolam and TBI + high dose midazolam + flumazenil) |
Single point drug administration at 24-h post TBI. | Midazolam did not have any effect on the lesion volume measured at 72-h post TBI. Midazolam impaired neurological recovery assessed through NSS score (40) at 72-h post injury. |
| Diazepam (22) | Electrolytic lesion. Long Evans hooded rats n = 16 for TBI group and n =8 for sham group. In each group half of the animals were undrugged. |
Drug administration at 10–12-h post TBI and continued till 22 days (intra-peritoneal injection). | Diazepam had no effect on the lesion size. Diazepam impaired recovery from sensory asymmetry as long as 22 days post injury. |
| Diazepam (41) | Electrolytic lesion. Long Evans hooded rats n = 9 and 7 for TBI (anterior-medial neocortex) groups receiving diazepam and vehicle, respectively. n = 9 and 9 for TBI (sensorimotor neocortex) groups receiving diazepam and vehicle, respectively. N =14 for sham operated animals |
Drug administration at 10–12-h post TBI and continued till 21 days (intra-peritoneal injection). | Increased atrophy of the striatum and cell death in the substantia nigra pars reticulata was observed in diazepam treated injured (anterior-medial cortex) animals. Diazepam treatment impaired recovery from sensorimotor asymmetry as long as 91 days post injury following anterior-medial cortical lesion. |
| Diazepam (42) | Central FPI Sprague-Dawley rats n = 8 each for TBI + diazepam, TBI + saline and sham operated controls (pretreatment). For post-treatment, n = 6 for TBI + diazepam and n = 5 for TBI + saline. |
Drug administration at 15 min prior or post TBI induction (intra-peritoneal injection) | Rats that were subjected to diazepam pretreatment had reduced mortality rates. Both pre and post treatment with diazepam assisted in cognitive recovery assessed through MWM test at 10–15 days post TBI. |
| Pentobarbital (19) | CCI Sprague-Dawley rats n = 9 for each experimental drug group (diazepam, fentanyl, morphine, isoflurane, ketamine, pentobarbital, ketamine, no anesthesia and sham) |
Drug administration for 1-h post TBI. | No effect on histological outcome after pentobarbital administration at 21 days post TBI. Pentobarbital did not help in recovery of motor or cognitive function assessed at various time points post TBI. |
| Phenobarbital (23) | Electrolytic lesion. Long Evans hooded rats for three groups: TBI + low dose (n = 3), TBI + high dose (n = 4) and TBI + NaCl (n = 6) |
Drug administration (2 times a day) at 48-h for up to 7 days post TBI (intra-peritoneal injection). | Phenobarbital treatment did not have any effect on the lesion volume. Phenobarbital treatment impaired recovery from sensorimotor asymmetry as long as 45 days post injury (no dose-dependency noticed). |
| Isoflurane (19) | CCI Sprague-Dawley rats n = 9 for each experimental drug group (diazepam, fentanyl, morphine, isoflurane, ketamine, pentobarbital, ketamine, no anesthesia and sham) |
Drug administration for 1-h post TBI. | Isoflurane administration led to better hippocampal neuronal survival rates at 21 days post TBI. Isoflurane resulted in recovery of cognitive function assessed by MWM test at 14–20 days post TBI. |
| Isoflurane (21) | CCI Sprague-Dawley rats n = 9 for each experimental drug group (isoflurane and fentanyl) and (n = 6) for each sham anesthetic group |
Continuous drug administration before TBI and continued till 3.5–4-h post TBI. | Isoflurane resulted in better hippocampal neuronal survival rates (estimated at 21 days post TBI) compared to fentanyl although edema and ICP were similar. Isoflurane resulted in superior motor (1–5 days) and cognitive function recovery (14–20 days) compared to fentanyl. |
| Isoflurane (43) | CCI Sprague-Dawley rats n = 9 for each group tested (isoflurane, fentanyl and recovery with no anesthesia) |
Continuous drug administration before TBI and continued till 1-h post TBI. | Compared to fentanyl, isoflurane resulted in better hippocampal neuronal survival rates (21 days post injury). Isoflurane resulted in better functional recovery compared to fentanyl (1–20 days post injury). |
| Isoflurane (20) | CCI C57BL/6N mice n = 6 for each group tested [isoflurane, sevoflurane and combo (midazolam, fentanyl, medetomidine)]. Two such cohorts were utilized for histology at 15 min and 24-h post TBI |
Continuous anesthesia initiated before TBI and stopped right after injury induction. | Isoflurane resulted in reduced contusional volume measured at 24-h post injury. Isoflurane also resulted in better recovery of neurological function measured by NSS test (40) at 24-h post TBI. |
| Isoflurane (44) | CCI C57BL/6J mice receiving avertin (n = 78) and isoflurane (n = 57) anesthesia |
Animals received a single impact or 2–3 repeated impacts with 48-h gap. Anesthesia applied prior to surgery. | Isoflurane resulted in reduced axonal injury compared to avertin anesthesia at 24-h post TBI. |
| Isoflurane (45) | CCI Rats TBI + short anesthesia (n = 20) TBI + long anesthesia (n = 30) |
Short anesthesia for 30 min (at 7.5-h post TBI) and longer anesthesia for 4 (at 4-h post TBI) hours was administered. | Prolonged anesthesia resulted in higher edema formation immediately after injury. |
| Isoflurane (46) | CCI C57BL/6J mice n = 7 for each group mentioned below: CCI + isoflurane CCI + sevoflurane Sham + isoflurane Sham + sevoflurane |
Anesthesia was started prior to CCI and continued for 15–20 min during injury induction. | Edema formation was higher in isoflurane treated animals compared to sevoflurane at 24-h post TBI. |
| Isoflurane (47) | CCI Sprague-Dawley rats CCI + isoflurane (normal sedation, n = 12) CCI + isoflurane (deep sedation, n = 12) |
Anesthesia was maintained for 2-h prior to CCI. | Deep anesthesia resulted in increased neurodegeneration and poor functional performance estimated at 48-h post TBI. |
| Topiramate (48) | Lateral FPI Sprague-Dawley rats TBI + drug (n = 35) TBI + saline (n = 25) Sham + drug (n = 21) Sham + saline (n = 26) |
Drug given at 30 min, 8, 20 and 32-h post TBI (intra-peritoneal injection). | Topiramate did not have any effect on the volume of the contusional tissue (1-month post TBI) and edema formation (48-h post TBI). Topiramate resulted in better recovery of motor function (4 weeks post TBI) but affected cognitive learning (4 weeks post TBI). |
| Vigabatrin (49) | Electrolytic lesion. Long–Evans hooded rats. n = 7, 9, 8, 11, respectively for brain injured animals receiving low, medium, high drug dose and saline. n = 9, 9, 9, 10, respectively for sham animals receiving low, medium, high drug dose and saline |
Drug given at 48-h post TBI and continued for 7 days (intra-peritoneal injection). | Vigabatrin treatment did not have any effect on the lesion volume. Vigabatrin did not have any effect on recovery of sensory function post TBI (assessed up to 60 days post injury). |
The table includes the model of TBI induction, drug administration timeline, and experimental groups along with the reported histopathological outcomes and effect on functional recovery.