Propofol effects in rodent models of traumatic brain injury: a systematic review

We selected articles that met the inclusion criteria, which were a trial using a rodent model of TBI, with propofol as one of the intervention agents. We also included articles comparing the neuroprotective effects of propofol with other agents in rodent models of TBI. We excluded articles that were not available in full-text form and studies that were not published in English.

Relevant publications were identified using PubMed, EBSCO Host, and ProQuest search engines without restrictions or filters of publication date or language. The search keywords included MeSH: propofol, TBI, traumatic brain injury, neuroprotection, neuroprotective agents, and rodents. In addition to the MeSH keywords, we also added 2 other keywords not listed in the MeSH: neurotoxicity and craniocerebral trauma. A reference search from selected articles was conducted manually. All study searches were completed by March 1, 2021.

Data was extracted from the selected studies by 2 reviewers independently using Cochrane standardized data extraction form [14]. Data extracted from each study included year of publication, study design, study objectives, number of experimental groups, analytical methods, stated limitations and recommendations, and the study conclusions. A validity assessment was also conducted using the Cochrane risk-of-bias tool [15]. All data extracted from the selected studies were compiled into a table and explained qualitatively.

Based on the search strategy described above, 13,540 studies were found. After duplicates were removed, 9,286 studies remained, and prespecified criteria excluded 2,018 more studies, leaving 7,268. Then, these studies were screened by reading the titles and abstracts of each study, and 17 relevant studies were obtained. Of the 17 studies, we evaluated eligibility and feasibility of data extraction with a standardized form and found 12 that met the requirements for data extraction and further analysis (Figure 1).

Figure 1

The assessment was conducted using the inclusion criteria. Overall, the study findings show a large variety of trauma types and methods used to evaluate the effects of propofol. The research methods and designs used were heterogeneous. Most of the researchers did not explain the bias that might occur in their respective studies [16, 17, 18, 19]. Only 3 articles described the bias that could affect the results of the study they reported [20, 21, 22]. Moreover, only one study used investigators blinded to the treatment during the intervention process and the assessment of intervention results [23].

Characteristics of the included studies are shown in Table 1. Of the 12 studies included in the present research, 8 assessed the physiological parameters of experimental animals. Mean arterial pressure (MAP), heart rate, pH, PaCO₂, and PaO₂ were not found to be significantly different in 4 studies, both in the pre- and post-trauma evaluation, and the evaluation in each experimental group. Another 3 articles did not state whether there was a change in physiological factors during the experiment, and the remaining article reported differences found in physiological parameters that were affected by the dose of propofol administered [16, 18, 19, 20, 22, 23, 24, 25, 26]. Apart from the previously mentioned physiological parameters, studies by Sebastiani et al. [23], Statler et al. [24], and Thal et al. [25] also assessed core temperature, brain tissue temperature, hematocrit, and serum glucose levels in rats or mice during the experimental procedure, all of which were within normal limits, and there were no differences found between groups.

A significant reduction in lesion volume after administration of propofol was found in 2 studies. The volume reduction effect is stronger when propofol is given early [17, 22]. No change in lesion size after administration of propofol was found in another 2 studies, even when low dose (20 mg) and high dose (30 mg) of propofol were administered to investigate a possible dose-dependent effect [16, 25]. Sebastiani et al. [23] found that early propofol administration (6 h post injury) did not substantially influence lesion volume. Meanwhile, delayed propofol administration (24 h after exposure to trauma) was associated with significant increase of lesion volume in a mouse group with propofol sedation compared with a control group. Statler et al. [24] found propofol increases lesion size in adult rats, as do other anesthetic agents. There was no lesion size data for the remaining 6 studies.

From the studies analyzed, we found 3 that assessed the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in rats administered propofol and found an increase in SOD levels and a decrease in MDA levels in brain tissue [20, 21, 27]. However, Öztürk et al. [27] did not find a significant difference in SOD levels. In addition to SOD and MDA levels, Öztürk et al. [27] also measured the levels of xanthine oxidase (XO), levels of nitric oxide (NO), and catalase activity (CAT) in brain tissues. CAT levels were not found to be significantly different between the groups, while XO and NO levels were lower in the propofol group. The difference in NO levels was significant, while XO levels were not. Ma et al. [21] measured glutathione (GSH) levels, another indicator in assessing the oxidative stress response, which were elevated after propofol administration.

Inflammatory factors such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are released spontaneously in brain tissue after TBI, but propofol can reduce their levels. Ding et al. [17] specifically described the release of IL-1β and TNF-α and the effect of propofol on pyrrolidine dithiocarbamate (PDTC) activation pathway as an inhibitor of nuclear factor kappa B (NFκB) and SB203580 as an inhibitor of P38 mitogen-activated protein kinases (p38/MAPK), which was used to assess specific pathways of aquaporin-4 (AQP-4) expression. Propofol acts as an inhibitor of both the NFκB and p38/MAPK pathways. qRT-PCR analysis found that propofol clearly inhibits the expression of the AQP-4 mRNA in vivo, which is mediated by NFκB. This inhibition by propofol is influenced by the dose given and the time of administration. The explanation for the timing of administration effectiveness relates to activation of acute transcription of AQP-4 after the onset of TBI [17]. A decrease in the levels of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome occurred after propofol administration in rats. The levels of IL-1β and TNF-α in the cerebral cortex tissue increased in the first 12 h and 24 h after trauma, while propofol administration at the time of trauma decreased release of these inflammatory factors [21]. After the administration of propofol, the expression of IL-1β, IL-6, and TNF-α mRNA decreased inflammation in rats compared with an experimental group without propofol administration. After the administration of propofol, the protein levels of the 3 cytokines were significantly decreased [19]. Based on these 3 studies, we infer that propofol exerts neuroprotective effects by reducing inflammatory factors [17, 19, 21].

Sebastiani et al. [23] found propofol had neurotoxic effects through calpain activity increase as seen from the quantification of αII-spectrin degradation results. Calpain or calcium-regulated cysteine protease promotes cell death. The amount of αII-spectrin degradation was not affected by propofol in the first hour after trauma, but increased significantly in the following 6 h. Moreover, propofol administration expanded lesions because of TBI via a neurotrophic receptor pathway by mediating an increase of pro-brain-derived neurotrophic factor-p75 levels. Yu et al. [26] found propofol had the opposite effect. After propofol administration up to 4 h after TBI, the quantity of αII-spectrin degradation products was significantly lower in the pericontusional cortex of rats at 24 h after TBI compared with vehicle control, although we note the use of chloral hydrate in their model which is unacceptable for anesthesia.

Neurological function has been assessed based on the motor and cognitive functions of rat models. Motor function in rats was assessed by beam balance and beam walking tests. The rats from both propofol-administered and control groups showed disturbances in motor function after injury. However, Statler et al. [24] showed that rats in a group given propofol showed more severe impairment than the control group. Thal et al. [25] also showed that motor impairment was more severe in rats administered larger doses (72 mg/kg/h) of propofol. Cognitive function was assessed using the Morris Water Maze (MWM) and Barnes maze tests [24, 25]. In the MWM, rats in the propofol group showed slower learning ability than a control group [24]. The Barnes maze test results varied greatly between rats; and the investigators were unable to show any significant differences between groups [25]. Lou et al. [22] found no significant changes on MWM assessment on days 14 and 17 after TBI followed immediately by propofol administration.

The doses of propofol administered in the various studies differed widely, as did the route of drug administration. In 5 studies, the dose range for bolus intraperitoneal administration of propofol ranged from 50 mg/kg to 100 mg/kg [17, 19, 20, 21, 27]. However, standard administration of propofol is by intravenous infusion. In another 5 studies, intravenous administration with doses varying from 10 mg/kg/h to 85 mg/kg/h were used. Yu et al. [26] used intravenous bolus. It is not clear which dose of propofol caused neuroprotective effects nor is it clear which dose causes neurotoxic effects [18, 23, 24, 25, 26].

Propofol administration often causes side effects in the form of hypotension. Hypotension is categorized as a mild side effect when compared with the advantages of propofol which can maintain cerebral perfusion pressure in patients with TBI [28]. Propofol did not show any significant effect on the physiological parameters of rodents that underwent experimental TBI, either before or after the trauma [16, 18, 20, 22, 23, 24, 25, 26]. These findings are consistent with data on propofol in humans, which shows a good safety profile [28, 31, 32]. Statler et al. [24] explored the duration from trauma to extubation, and found rats administered propofol required a significantly longer time to extubation than those administered isoflurane, rats in a sham group, and rats that did not receive additional anesthetic agents.

Controlled cortical impact (CCI) type trauma in rodent models of TBI produced an increase in the volume of brain lesions after 24 h [33]. Histological assessment by Luo et al. [22] found a decrease in the volume of lesions after administration of propofol compared with that after administration of isoflurane. However, Eva et al. [16] found that the use of propofol did not affect lesion volume when compared with halothane as the anesthetic agent. The difference in the results might be a consequence of differences in the weight of the rats and the type of head injury. The overall primary injury lesion volume found by Thal et al. [25] was 23.8 ± 7.4 mm³, although not all data were shown. This study found no significant differences in lesion volume associated with propofol administration. Propofol administration within 24 h post trauma has shown an effect of increasing the lesion volume. However, the administration of propofol within 6 h produced no significant increase of lesion volume [23].

Secondary injury in TBI results in many pathophysiological effects, such as ion imbalance, inflammation, apoptosis, endoplasmic reticulum stress, and oxidative stress [34]. Oxidative stress itself produces reactive oxygen species (ROS) and causes a redox imbalance, producing LP, nucleic acid oxidation, and DNA damage leading to neuronal damage and neuron cell death [35]. Lipid peroxidase activity is assessed by the level of MDA, and the changes in cerebral cortex endogenous antioxidants post TBI can be assessed based on levels of SOD and GSH. As expected, propofol administration increased the activity of SOD and GSH, which would decrease MDA levels in the process of oxidative stress [21]. In the present review, we found propofol administration reduced oxidative stress by attenuating microglia activation, MDA, and NO levels.

The inflammatory response after TBI will activate microglia and astrocytes, release inflammatory mediators in the brain, and mobilize peripheral immune cells (e.g., leukocytes and monocytes). Biomarkers commonly used for anti-inflammatory and proinflammatory molecules are TNF-α, IL-1β, IL-6, IL-8, and IL-10 [36]. Propofol can decrease neurological damage by suppressing the inflammatory reaction, with the inflammatory cytokines most affected by propofol administration being IL-1β and TNF-α [17, 19, 21]. Overactivation of the NLRP3 inflammasome after trauma in the cerebral cortex affects the neuroinflammatory processes leading to secondary trauma. Propofol can mitigate the inflammatory response, reduce brain damage by inhibiting ROS production and depress activation of the NLRP3 inflammasome, and influence the expression of proinflammatory cytokines [21]. The glymphatic system plays a role in directing cerebrospinal fluid to enter the brain through the periarterial space, into the interstitium via AQP-4. After TBI, the function of the glymphatic pathway is impaired and decreases by up to 60% [36]. Administration of propofol immediately after TBI reduces edema and will inhibit the overexpression of AQP-4 [17].

Apart from the direct effect of propofol on neurotrans-mission, propofol also results in impaired mitochondrial function in neurons, which is responsible for neurotoxicity and postoperative brain dysfunction. During the anesthesia, propofol inhibits electrophysiological processes that can inhibit ATP requirements [37]. Sebastiani et al. [23] demonstrated that immediate administration of propofol after acute injury produces an adverse effect mediated by pro-brain-derived neurotrophic factor-p75. By contrast, propofol also increases calpain activity as seen from the high degradation result of αII-spectrin by the calpain-dependent proteolysis mechanism. Increased degradation of αII-spectrin by calpain-dependent proteolysis is thought to be a mechanism for propofol-induced neurotoxicity in the developing brain that results in structural changes, changes in synaptic plasticity, and activation of the cell death process [23]. By contrast, Yu et al. [26] did not find a neurotoxic effect of propofol. The significantly lower level of αII-spectrin degradation in the propofol group suggested that propofol was active and neuroprotective in the calpain activation pathway in TBI.

A strong adverse effect of propofol administration is a decrease in the post-traumatic neurogenesis process, especially if it is administered within a few hours post trauma. The brain will undergo physiological changes to maintain and enhance neurogenesis during TBI, whereas the process will be hindered by propofol infusion. Neurogenesis has an important role in memory function. The inhibition of neurogenesis results in a decrease in cognitive and motor function in both humans and rats [24, 25]. Statler et al. [24] showed that rats given propofol experienced more severe impairment than a control group [24]. Thal et al. [25] also showed that motor impairment was more severe in rats receiving propofol in larger doses. Impaired cognitive function on MWM assessment as an indicator of hippocampal damage can be measured by counting the number of neurons in the region. Luo et al. [22] found no significant difference of propofol administration in improving cognitive abilities according to a MWM test, as consistent with the state of TBI, which induces neuron cell death.

We did not limit the present review by the type of TBI. Therefore, the conclusions drawn are the result of general analysis and are not limited to particular types of TBI. Moreover, some of the literature analyzed reported propofol administration before and during the trauma (not only after the trauma process occurred). This may have biased conclusions on assessing the effects of propofol, which is most commonly used after trauma occurs.