L-Carnitine prevents memory impairment induced by post-traumatic stress disorder

Abstract

Background:

Post-traumatic stress disorder (PTSD) is a genuine obstructing mental disorder. As indicated by the name, it is related to the patients’ stress augmented by life-threatening conditions or accidents. The PTSD has linked to oxidative stress that can result in neurodegeneration. L-carnitine (L-CAR) is known for its antioxidant properties, which can protect against neuronal damage.

Objective:

In the current study, we investigated the beneficial effects of L-CAR on the memory impairment induced by PTSD using a rat model.

Methods:

A model of single-prolonged stress (a cycle of restraining, forced swimming, rest, and finally diethyl ether exposure for 2 h, 20 min, 15 min, and 1–2 min, respectively) was used to induce PTSD-like behavior. Intraperitoneal L-CAR treatment (300 mg/kg/day) was introduced for four weeks. Both memory and special learning were evaluated utilizing the radial arm water maze (RAWM). Moreover, the levels of glutathione peroxidase (GPx), glutathione reduced (GSH), and glutathione oxidized (GSSG) were assessed as biomarkers oxidative stress in the hippocampus.

Results:

The results demonstrated that both the short and long-term memories were impaired by PTSD/SPS model (P < 0.05), while L-CAR treatment prevented this memory impairment in PTSD rats. Besides, L-CAR prevented the reduction in GPx activity and increase in GSSG, which were altered in the hippocampus of the PTSD/SPS rats (P < 0.05). Levels of GSH were not changed in PTSD and/or L-CAR rats.

Conclusions:

L-CAR administration prevented short- and long-term memories’ impairments induced in the PTSD/SPS rat model. This is probably related to its antioxidant effects in the hippocampus.

Keywords

Post-traumatic stress disorder L-carnitine memory impairment oxidative stress antioxidants hippocampus

1 Introduction

Post-traumatic stress disorder (PTSD) is one of the incapacitating, widespread, and hard-to-treat mental disorders (Amani et al., 2019). Victims can develop this disorder after being exposed to extreme traumatic events like those people who witnessed wars and natural disasters (Compean & Hamner, 2019). PTSD causes both molecular changes and psychological symptoms (Jakel, 2020). It resulted in functional impairment of the social or family life of the patients, including work unsteadiness, marital problems, and other social problems (Miao et al., 2018).

L-carnitine (L-CAR) can be generated naturally by the human body, yet it is regularly taken as a dietary supplement (Ferreira & McKenna, 2017). The L-CAR is essential in the fatty acids β-oxidation process where it can affect the function, structure, and even the turnover of specific cellular proteins and peptides through critical acetylation of some of the functional groups of their structural amino acids especially the -OH and the -NH2 groups at the N terminal amino acids (Carillo et al., 2020).

Other reported effects of L-CAR included neurobiological effects that comprise brain energy modulation, the metabolism of cellular macromolecules including phospholipids, neurohormones, and neurotrophic factors (Traina, 2016). It also can affect the synaptic transmission of multiple neurotransmitters and ultimately can change the synaptic morphology (Ferreira & McKenna, 2017). As well, L-CAR was reported to possess valuable effects in neurodegenerative disorders such as Alzheimer’s dementia (Pennisi et al., 2020). Feeding L-CAR to old rats enhanced the execution of memory assignments, and cause a significant reduction in the oxidative destruction and the structural decay of the brain mitochondria (Liu et al., 2002). Moreover, administration of L-CAR is considered protective against aging process through maintaining the mitochondrial bioenergetics and limiting the deteriorating effects of age-related oxidative damage (Traina, 2016). This effect is thought to be related to the ability of L-CAR in preserving the cellular repertoire of the endogenous antioxidants such as glutathione (GSH) especially in astrocytes and in up-regulating critical molecules for the aging process. Besides, the expansion in GSH has other functional protective effects on the neuronal mitochondria including the preservation of sufficient neuronal networking and a significant reduction in the Ab1–42 induced apoptosis (Abdul et al., 2006).

The current study focused on determining the modulatory effect of L-CAR against the development of PTSD-induced memory impairment in a rat model. As well, the effect of this supplement on the levels and function of specific antioxidants in the brain hippocampus were investigated.

2 Methods

2.1 Animals and treatments

Adult male Wistar rats with weight ranges 200–250 g were provided by the animal care facility at Jordan University of Science and Technology. The rats were housed in plastic cages (3 rats/cage) under hygienic conditions at 24±2°C, with accessible food and water and 12 h light/dark cycle. The experimental protocol of the current study was approved by Animal Care and Use Committee (ACUC) at Jordan University of Science and Technology (approval number 109/2018). Using a parallel groups design, the studied rats were randomly assigned into 4 different groups (N = 15 rat/ each group). The control group received daily intraperitoneal normal saline without exposure to single prolonged stress (SPS) procedure or L-CAR administration. The L-CAR group were treated with intraperitoneal L-CAR (300 mg/kg/day). This dose was used in previous studies and has been shown to be effective against cognitive function impairment in conditions other than PTSD (Alzoubi, 2017; Muthuswamy et al., 2006; Rababa’h et al., 2019; Tsakiris et al., 2008). The PTSD group was exposed to the single-prolonged traumatic stress and was treated with intraperitoneal normal saline. Finally, the PTSD and L-CAR (PTSD/L-CAR) group was exposed to single-prolonged stress procedure and administered L-CAR as described above. The single-prolonged stress procedure was instituted on day 1 of the experiments, whereas the L-CAR treatment was started at day 1 and continued daily for 28 days (4 weeks) including the day of the behavioral testing. All treatments were applied during the morning shift.

2.2 Induction of single prolonged stress model (SPS)

The SPS procedure included the following: animals were firstly restrained for two hours. Then, they were wrapped by duct tape to guarantee full immobility as previously described (Ahmed et al., 2020; Alquraan et al., 2019). After that, animals were forced to swim in a transparent cylindrical receptacle for twenty minutes. When finished, rats were retained in a cage for 15 minutes to rest. Lastly, each rat was exposed to ether anesthesia for few minutes until loss of consciousness (Li et al., 2010; Patki et al., 2014; Yamamoto et al., 2009).

2.3 Behavioral test

In this study, the spatial learning and memory were measured using the radial arm water maze (RAWM) as detailed elsewhere (Alzoubi et al., 2014; Alzoubi , 2013; Alzoubi , 2013; Park et al., 2008). This procedure was performed for all groups. During this procedure, the number of errors each animal made until completing the RAWM task -finding the hidden platform- was assessed. The observer researcher who scored the number of errors was blinded to the experimental groups.

2.4 Hippocampus dissection

All rats were sacrificed by decapitation at the end of the 28 days treatment. Directly after decapitation, brain dissection was performed and isolated. Thereafter, the dissected brain was put over a filter paper previously soaked with normal saline. The brain was kept cold by placing the filter paper over a cold dissecting surface. The hippocampus was removed directly and then transported to formerly labeled Eppendorf tubes. Then, this Eppendorf tube was reserved in liquid nitrogen and finally saved at (–30°C) until it is used during the time of analysis (Khabour et al., 2013).

2.5 Calorimetric enzymatic assays

To determine the levels or activities of the oxidative stress biomarkers, the obtained hippocampus samples were manually homogenized using a plastic pestle apparatus and resolved in 200μl of phosphate buffer (lysis buffer) made by reconstitution of one tablet of phosphate buffered saline (Sigma Chemical CO., Saint Louis, MO) and two protease inhibitor tablets (Sigma Chemical CO., Saint Louis, MO) in 200 ml of distilled water. To remove insoluble materials, only the supernatant was retained after applying proper centrifugation (14,000xg for 10 minutes at 4C°). The supernatant was, then, stored at –30°C for further examination. The whole work was carried out over crushed ice. The total protein concentration was determined in each sample using an existing commercial kit (Bio-Rad, Hercules, CA, USA). Commercially available kits were used to measure GSH and GSSG (Glutathione Assay Kit, Sigma–Aldrich Corp), and GPx (Sigma–Aldrich Corp) according to manufacturers’ recommendations and as previously described (Alzoubi, 2019; Alzoubi, 2020).

2.6 Statistical analysis

GraphPad Prism software (version 4.0) was used to run the statistical analysis. The two-way ANOVA statistical test was used to compare the number of errors and then followed by the Bonferroni posttest. Time (repeated measures factor) and treatment (between-subjects factor) groups were the independent variables. The one-way ANOVA test: followed by the Bonferroni posttest was used to compare immunoassays results. P < 0.05 was considered statistically significant, and the values were reported as mean±SEM.

3 Results

3.1 The effect of L-CAR treatment on learning and memory

The number of errors during the initial learning trails were high in all the study groups. Thereafter, with the trials’ repetition, the numbers of errors were lower. In all twelve learning trails, the number of errors committed by animals were not different among all the experimental groups (p > 0.05, Fig. 1).

Fig. 1

Performance of animals during RAWM. Comparison of performance of rats during the acquisition phase. The number of errors made by each animal declines with continuous learning without significant difference among all groups. Each point is the mean±SEM of 15 rats.

During the short-term memory test (which was completed for 30 minutes after the finish of the twelfth learning trial), a similar number of errors were made by the control, L-CAR, and the PTSD/L-CAR groups. However, in the PTSD group, a significantly higher number of errors were reported in comparison with the other groups (p > 0.05, Fig. 4.2A). This demonstrated that the L-CAR treatment modulated the impairment of the short-term memory that was induced by applying the PTSD model. As well, L-CAR administration had no effects on cognitive functions in normal rats, thus, emphasizing its protective role of L-CAR against the chronic PTSD-induced memory impairment.

Fig. 4

Effect of L-CAR and PTSD on the levels of GSH and GSSG in the hippocampus: (A) Hippocampal GSH Levels: there is a significant elevation in the levels of GSH amongst all experimental groups. (B) Hippocampal GSSG levels: The PTSD group showed a significant elevation in the hippocampal GSSG level compared to other groups, L-CAR treatment normalized the increment in the GSSG level in PTSD rats. Each point is the Mean±SEM of 15 rats. ^*Indicates a significant difference compared to other groups (P < 0.05).

Regarding the long-term memory tests, which were conducted after 5hrs and 24hrs of the end of the learning phase. Again, the L-CAR administration was sufficient in preserving the errors numbers after the PTSD (PTSD versus all other groups: P < 0.05, control versus PTSD/L-CAR: P > 0.05; Fig. 2).

Fig. 2

Short-term (30 min) memory test, and long-term memory tests (5hrs and 24hrs). PTSD group showed a significant elevation in many errors compared to other groups. Administration of L-CAR protects animals from short-term and long-term memory deficits, (P < 0.05).

3.2 The effect of L-CAR treatment on the oxidative stress biomarkers of the hippocampus

3.2.1 Hippocampus glutathione peroxidase (GPx) activity

The hippocampus in the PTSD group has a significantly decreased activity of the GPx in comparison to all other group (P < 0.05; Fig. 3). The L-CAR treatment alone in control rats did not affect the GPx activity, however, this treatment in the L-CAR/PTSD group preserved the GPx activity close to that in the control group and prevented its significant reduction that was noticed in the chronically challenged PTSD rats.

Fig. 3

Hippocampal GPx Activity: GPx activity was approximately similar in the hippocampus among all groups. Comparison of control, L-CAR, PTSD, and L-CAR/PTSD. Significant reduction in GPx activity in the PTSD group compared to other groups, Chronic treatment with L-CAR normalized activity of GPx during PTSD. GPx levels were not affected in naïve rats treated with L-CAR. Each point is the mean±SEM of 15 rats. ^*Indicate a significant difference (P < 0.05) compared to other groups.

3.2.2 Levels of GSSG and GSH

No significant changes were detected in the levels of GSH between the different animal groups (P > 0.05, Fig. 4A). The PTSD resulted in increase in the levels of GSSG compared to the control, L-CAR and PTSD/L-CAR groups (P < 0.05, Fig. 4B). The L-CAR treatment showed an ability to prevent these increases the levels of GSSG (Fig. 4).

4 Discussion

The present study investigated the delineating potential and defensive effects of L-CAR treatment on the cognitive impairments induced by the PTSD-like rat model. The findings of the current study illustrated that PTSD could induce impairments in both short-and long-term memories, which was prevented by L-CAR chromic treatment. This could possibly be related to the antioxidant properties of L-CAR.

The current results on the effect of the SPS/PTSD model on the cognitive disfunction were compatible with the findings by other studies using either the RAWM (Patki et al., 2014) or the Morris water maze (Wang et al., 2010; Wen et al., 2015). However, learning ability was not defective by the SPS/PTSD rat model as, with time, the learning ability of the studied animals revealed progressive improvements (Alquraan et al., 2019; Alzoubi, 2017). On the other hand, both the short-and the long-term memory impairments were impaired by the administration of the L-CAR treatment in the L-CAR/PTSD animal group.

In fact, traumatic/injured incidents leading to PTSD can adversely affect individuals since they corresponded with numerous comorbid conditions, including memory impairment, depression, and anxiety. The exact main pathophysiological pathway of PTSD is not unequivocal so far; various mechanistic changes on the molecular level were suggested to occur (Sin et al., 2017).

Increasing the hippocampal oxidative damage and its consequent impairment of memories was demonstrated using the PTSD model. For instance, foot shock and maternal partition (Diehl et al., 2012), single prolonged stress (SPS) (Alzoubi, 2018; El-Elimat et al., 2019; Solanki et al., 2015), predator exposure/ psychological stress (Alzoubi, 2020; Rababa’h et al., 2019), and inescapable foot shocks (Sun et al., 2016). In comparison with previous investigations, current outcomes were predictable. As such, current results demonstrated an obvious reduction in the antioxidants capabilities, particularly GPx, of the hippocampus after PTSD, and demonstrated significant enhancement of the GSSG levels. These outcomes agreed with the consensus that oxidative damage can lead to brain neuronal brain destruction and memory impairments (Ahmed et al., 2020; Alzoubi, 2018). Besides, current outcomes assured that L-CAR treatment most importantly reestablished and normalized the hippocampal GPx movement, GSH, and GSSG impairment caused by SPS model of PTSD and therefore caused significant modulation in the hippocampal antioxidant mechanisms.

Oxidative damage is accompanied by cognitive impairments in numerous diseases, for example, Alzheimer’s disease (Lauderback et al., 2001; Lovell & Markesbery, 2001; Markesbery & Lovell, 1998; Markesbery, 2005), traumatic brain injury (Wu et al., 2010), western diet use (Alzoubi , 2013), hyperhomocysteinemia (Alzoubi et al., 2014) sleep deprivation (Alzoubi, 2019; Alzoubi, 2019; Alzoubi, 2017), and aging (Nicolle et al., 2001). Previous and ongoing studies demonstrated that PTSD diminished antioxidant mechanisms, particularly, GPx and GSH, increased GSSG levels, and cause impairments on both short-and long-term memories Strong support to this conclusion came from these outcomes that demonstrated their role in causing cognitive impairments and critical damage to the brain cells related to oxidative stress under different pathological conditions and disease states including PTSD (Alzoubi, 2018; Alzoubi, 2017; Alzoubi, 2018; Borovac Štefanović et al., 2015).

In the current study, we demonstrated that normalizing the oxidative damage, that is initiated by PTSD, using the administration of L-CAR can modulate the memory impairment in its short- and long-term phases. L-CAR is a characteristic constituent of all mammalians. It is quaternary ammonium aggravate that is water-dissolvable and naturally functional in the l-isoform (Carillo et al., 2020). Previous limited studies were used to assess the modulating effects of acetyl-l-carnitine on memory and learning impairments prompted by various disease conditions. For instance, L-CAR manifests antioxidant capabilities and has neuroprotective properties in maturing animals (Alzoubi, 2017; Rababa’h et al., 2019). The treatment with L-CAR enhance changes in the amounts of some of the antioxidant markers including GPx, catalase, and SOD (Alzoubi, 2017; Rababa’h et al., 2019). The metal chelating and the antioxidant capabilities of L-CAR can explain the increased SOD activity upon the treatment of PTSD (Rani & Panneerselvam, 2002). On the other hand, the enhanced activity of G6PD and the consequent increase in NADPH levels upon L-CAR administration can explain the expansion in catalase activity (Alvarez et al., 1993). Moreover, L-CAR administration can assure a protective mechanism preventing the peroxidative destruction of those defense systems and endogenous antioxidants (Augustyniak & Skrzydlewska, 2010; Li et al., 2012). Additionally, many studies were performed to investigate the proposed activities of carnitines as neuroprotective agents in states of many disorders such as Alzheimer’s and Parkinson’s sicknesses and its underlying oxidative damages and mitochondrial dysfunctions (Pennisi et al., 2020). Furthermore, L-CAR was accounted to have neuroprotective activities against the neurotoxicities enhanced by 3-nitropropionic acid (3-NPA) (Virmani et al., 2003) where the CNS neurotoxicities accompanied with drugs abusing were constricted in animal or cell lab models when pre-treated with ALCAR (Virmani et al., 2003). Moreover, it was illustrated that L-CAR treatment in aged rats can ameliorate the oxidative stress in some of the parenchymal brain cells and consequently re-establish their cognitive functions (Aliev et al., 2009; Liu et al., 2002).

The molecular mechanisms of L-CAR inhibition and modulating the memory impairments induced in the PTSD model require promoted examination. L-CAR, through the modulation of the oxidative damage in the hippocampus, is proved to prevent the memory debilitation of PTSD rats. The present findings demonstrate that antioxidant biomarkers such as GPx and GSSG ratio are reestablished by L-CAR treatment during PTSD. In agreement with that, SOD, catalase, and GPx levels in the hippocampus of aged rats were significantly corrected when treated with L-CAR (Alzoubi, 2017; Rababa’h et al., 2019).

In conclusion, L-CAR could be a promising medication to be utilized to prevent memory impairments induced by PTSD. Chronic L-CAR administration has no influence on learning and spatial memory in naïve rats. Then again, L-CAR inhibits the hurtful consequences of PTSD on both, the short and the long-term phases of memory. These outcomes support our notion that L-CAR demonstrations just in a need-based manner (at the point of memory dysfunction).

In the hippocampus, PTSD impairs antioxidant mechanisms, for example, GPx, GSSG, though L-CAR secures antioxidant self-mechanisms activity as appeared by normalizing GPx, GSSG, and GSH activities. The mechanisms by which L-CAR prevents PTSD-induced memory impairment need further examination. We believe that L-CAR treatment disallows this impairment in memory by ameliorating the hippocampal oxidative damage of PTSD rats. Other biomarkers of oxidative stress need to be examined in future studies such as the capacity enzymes of catalase, and SOD, and lipid peroxidation pathway. Additionally, histopathological study is essential to examine the effects of L-CAR and/or PTSD on neuronal survival in the hippocampus.

Footnotes

Acknowledgments

The study was funded by grant no. 109/2018 to KA from the Deanship of Research of the Jordan University of Science and Technology.

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