GPR30 Agonist G1 Combined with Hypothermia Alleviates Cognitive Impairment and Anxiety-like Behavior after Subarachnoid Hemorrhage in Rats

doi:10.21203/rs.3.rs-2690468/v1

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GPR30 Agonist G1 Combined with Hypothermia Alleviates Cognitive Impairment and Anxiety-like Behavior after Subarachnoid Hemorrhage in Rats

https://doi.org/10.21203/rs.3.rs-2690468/v1

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This study aimed to investigate the treatment effect of G protein-coupled receptor 30 (GPR30) agonist G1 combined with hypothermia (HT) on the cognitive impairment and anxiety-like behavior after subarachnoid hemorrhage (SAH) in rats. Fifty male rats were randomly assigned to one of five groups: Sham group, SAH group, SAH+G1 group, SAH+HT group and SAH+G1+HT group. SAH rat model was established by modified endovascular puncture in all groups except the Sham group. Neurological function after operation was assessed by Garcia scoring. The degree of rat cerebral edema was determined using dry-wet weighing method 48h after operation. Moreover, the behavioral test was performed on rats on the 4^th and 28^th day after operation. Compared with Sham group, Garcia score of each SAH rat model group decreased significantly on the 1^st day and thereafter increased gradually. However, the recovery rate of each treatment group was higher than the SAH group (no treatment), and Garcia score of SAH+G1+HT group was much higher than the SAH group on the 7^th day after operation. In addition, each treatment group could obviously reduce the cerebral edema degree of SAH rats, among which rats in SAH+G1+HT group had lower cerebral edema degree than SAH+G1 group and SAH+HT group. Behavioral test results showed that the combination of GPR30 agonist G1 and hypothermia markedly improved the learning and memory ability of SAH rats, alleviated their anxiety- and emotion-related behavior and enhanced their social interaction. GPR30 agonist G1 combined with hypothermia reduces the cognitive impairment and anxiety-like behavior in rats with subarachnoid hemorrhage.

GPR30 agonist G1

Hypothermia therapy

Subarachnoid hemorrhage

Cognitive impairment

Anxiety-like behavior

Rats

Subarachnoid hemorrhage (SAH) refers to a clinical syndrome caused by a leakage of blood into the spinal subarachnoid space after rupture of blood vessels at the base or surface of the brain. It is a severe and common disease accounting for about 10% of factors causing acute stroke (Mahmoud and Mason, 2015). It is reported that about 80% of SAH is caused by rupture of aneurysm, and the remainder by vascular malformation and vasculitis(Chen et al., 2017). The early manifestations of SAH include sudden severe headache, nausea, vomiting, and meningeal irritation, with or without the presence of focal neurologic signs. In advanced patients, poor prognosis such as hemiplegia, aphasia, cognitive impairment and even death often occur, which is mainly associated with early brain injury and delayed brain injury caused by SAH(Jang et al., 2017). As an important feature of early brain injury, cerebral edema is an independent risk factor causing death and poor prognosis after developing SAH. Canial nerve injury after SAH, the main obstacle to the recovery of SAH patients, may cause cognitive ability decline and mental disorder such as anxiety and depression, and make it difficult for patients to return to work or live a functional life(Lawton and Vates, 2017).

Currently, superselective intra-arterial embolization or craniotomy clipping is the preferred treatment for SAH. However, the two treatment have side effects, and the effect of neurological function recovery after treatment still needs to be improved (Cruz et al., 2013). Mild hypothermia nursing is a method to phisically control the body temperature of the patient and inhibit vasogenic edema and bleeding, so as to regulate intracellular calcium ion aggregation and excitatory neurotransmitter release rate, maintain normal brain metabolism, and thus protect the neurological function(Thomé et al., 2005). However, the effect of mild hypothermia nursing alone is not enough to achieve the expectation. Therefore,the need for a more effective treatment for SAH is urgent. G protein-coupled receptor 30 (GPR30), a novel membranous estrogen receptor, can play the role of transcriptional regulation indirectly through the second messenger system(Bologa et al., 2006). A large number of clinical studies indicated that GPR30 plays a vital role in the regulation of neurological functions, such as neuroprotection, synaptic regulation, improvement of learning and memory ability, and neurogenesis(Dennis et al., 2011). G1, the specific agonist of GPR30, is effective in treating cardio-cerebrovascular disease due to its multiple functions. Studies found that G1 can alleviate neuronal apoptosis of male rats with SAH by activating src/EGFR/stat3/signaling pathway, thereby alleviating the brain injury(Peng et al.). It follows then that G1 may provide a prospective treatment strategy for SAH patients. However, there is still no studies reporting whether the combination of GPR30 agonist G1 and hypothermia can improve the cognitive impairment and anxiety-like behavior of SAH patients or not. Therefore, this study was proposed to explore the application effect of G1 or hypothermia alone or the combination of the two on cognitive impairment and anxiety-like behavior of SAH patient by establishing SAH rat model, in order to provide new strategy for the clinical treatment of SAH.

Establishment and grouping of rat SAH model

Totally 50 male SD rats (age: 6–8 weeks; weight: 180 ~ 220 g) were purchased from Shanghai Model Organisms Center, Inc. All rats were treated under the protocol approved by the the Institutional Animal Care and Use Committee and allowed for 1-week adaptation before the experiment. All experiments in this study were approved by Animal Ethics Committee of Haikou Affiliated Hospital of Central South University Xiangya School of Medicine (2022 − 200).

The rats were randomly divided into 5 groups: Sham group (n = 10), SAH group (n = 10), SAH + G1 group (n = 10), SAH + HT group (n = 10) and SAH + G1 + HT group (n = 10). The treatment for each group is as follows. SAH group: SAH model was established by modified endovascular puncture based on the modified modeling method of Guo et al.(Guo et al., 2016). Specifically, the rats were anesthetized by intraperitoneally injection of 1% pentobarbital sodium (Boster Biological Technology Co. Ltd) at a dose of 50 mg/kg. After the anesthesia, the rats were subjected to exposure of common carotid artery, external carotid artery and internal carotid artery, and then a nylon thread was used to run through the internal carotid artery. When the nylon thread reached the intracranial bifurcation, it was pushed further for 3 mm. After the puncturation of the blood vessel and the apical stitch, the blood flow was restored. SAH + G1 group: GPR30 agonist G1 (300 µg/kg, Gayman Company) was intravenously injected 1h after the establishment of SAH model. SAH + HT group: The rats were intermittently placed in a 5℃ cryogenic box 12 h after the establishment of SAH model and then fed for 12 h. The rectal temperature was kept at 32 ℃-34 ℃. SAH + G1 + HT group: GPR30 agonist G1 (300 µg/kg) was intravenously injected 1 h after the establishment of SAH model, and the rest operations were the same as the SAH + HT group. Sham group: After anesthesia of the rats, a midline incision of the neck was performed to expose the common carotid artery, external carotid artery and internal carotid artery. A nylon thread ran through the internal carotid artery and was pushed forward until it reached the neck. Notably, vascular puncture was not performed. Behavioral test of the rats was performed on the 4th and 28th day after the operation, whereafter, the brain tissue of the rat was extracted.

Garcia Neurological Function Score

The neurological function of rats in each group was evaluated using Garcia Scale(Garcia et al., 1995) before the operation and on the 1st, 3rd and 7th day after operation. This scale items included rats’ voluntary movement, activity symmetry of limbs, stretching ability of forepaws, ability of climbing and grasping the iron cage, physical sense reaction and reaction to beard touching. Rats with normal function had the highest score (18 points), and those with the most severely impaired function had the lowest score (3 points).

Determination Of Cerebral Edema Degree

Brain tissue was rapidly separated on ice from rats after deep anesthesia by intraperitoneal injection, and left and right cerebral hemispheres were taken. The wet weight of the brain tissue was measured by electronic analytical balance, and the tissue was baked in an incubator for 48 h. The tissue specimens were cooled for 10 min after being taken out from the incubator. Then its dry weight was weighed by the electronic analytic balance. The water content of the brain tissue was calculated using dry-wet weighing method, which is an index to evaluate the degree of cerebral edema (Li et al., 2015).

Behavioral Tests Of Rats

Morris water maze test (MWM): A 4-day training experiment was performed to evaluate the spatial learning and memory ability of rats in each group. The escape latency (1–4 days), number of entries in target quadrant, the time spent in the target quadrant and the average swimming speed of the rats were recorded. The worse the cognitive function of experimental rats, the longer the escape latency and swimming distance, the less the number of entries in target quadrant, the shorter time spent in the target quadrant(Bromley-Brits et al., 2011).

Novel object recognition test (NORT): The exploration time of rats in each group toward familiar objects (TF) and novel objects (TN) during the test phase was recorded. If the rat’s cognitive ability was bad, there was no difference between exploring time of TN and that of TF. If the rat’s cognitive ability was normal, the time spent in exploring TN would be longer than that in exploring TF. The recognition index (RI) of exploring novel objects was calculated as RI = TN/(TF + TN)(Leger et al., 2013).

Open field test (OFT): Rats were placed in the center zone of a black square device (100 cm×100 cm×40 cm). The free activity of the rats within 5 min were filmed by a camera and recorded by SMART software. Before the test, the rats were transported to the test room and allowed to adapt for 15 min. The noise in the room should be kept at 30 decibels and the light at 60 watts. The rats were placed in the center of the open field gently and allowed to explore for 5 min. The total traveled distance and time in the central zone were recorded. The total traveled distance reflected the movement of the rat, while the time in the central zone reflected the anxiety of the rat. The horizontal traveled distance and time in the central zone of depressed rat decreased significantly(Gould et al., 2009).

Elevated plus maze (EPM): The elevated plus maze was consisted of two open shelves (50 cm×10 cm×40 cm), central zone (5 cm×5 cm) and two closed shelves (50 cm×10 cm×40 cm) (CWE company). The rats were placed at the center of EMP and their tracks in 5 minutes were recorded by the camera and the software. Before the test, the rats were transported into the test room and allowed to adapt for 15 min. The noise of the room should be kept at 30 decibels. The maze was positioned 100 cm above the floor and the experiment was carried on in an environment as dark as possible. The rats were then placed at the center platform and the open arm entries of the rats and total time spent in open arm were recorded. The elevated plus maze reflected the anxiety of the rats. After receiving anti-anxiety drugs, the rats had an obvious increase in the open arm entries of the rats and the total time spent in open arm(Kraeuter et al., 2019).

Three-chamber paradigm test: An empty metal cage (E) was placed in the rightmost chamber and a strange rat of the same species (S) in a mental cage was placed in the leftmost chamber. The tested rat (placed in the center chamber) was allowed to move freely among the three rooms. The time the tested rat spent in the chambers on either side was recorded respectively to evaluate its sociability. Normal rats would spent more time in S chamber(Moy et al., 2004)

Reciprocal social interaction test: A tested rat and an S rat were simultaneously placed into a box (40 cm×40cm×30cm) and allowed to explore each other freely for 10 min. The number of bouts including crawl under and crawl over (push-crawl), nose-to-nose, anogenital investigation (nose-to-anogenital) and self-grooming behaviors was recorded(Matsuda et al., 2016).

Statistical analysis

SPSS 21.0 software was used for statistical analysis. T-test was used for comparison between two groups, whereas one-way analysis of variance for paired comparison among multiple groups. The results were expressed by mean ± standard deviation(SD). P < 0.05 was considered as the criterion for significant difference.

G1 combined with hypothermia improves the neurological function and alleviates cerebral edema degree of rats with subarachnoid hemorrhage

The results indicated that, there was no significant difference in Garcia score of rats in each group before operation (P > 0.05). On the 1st day after operation, the Garcia score of rats in each SAH model group decreased significantly (P < 0.05), and increased gradually thereafter. The recovery rates of all treatment group were higher than the SAH group. On the 7th day after operation, the Garcia score of the SAH group decreased markedly compared to the Sham group (P < 0.05), but there was no obvious difference in each treatment group (P > 0.05). The Garcia score of the SAH + G1 + HT group was notably higher than the SAH group (Fig. 1A). In addition, the results of the dry/wet ratio of brain tissue revealed that, the cerebral edema degree of rats in each SAH model group was much higher than the Sham group (P < 0.05). Compared to the SAH group, each treatment group displayed a significant decline in the cerebral edema degree of rats (P < 0.05). However, the cerebral edema degree of the SAH + G1 + HT group was lower than the SAH + G1 group and the SAH + HT group (P < 0.05) (Fig. 1B).

G1 Combined With Hypothermia Improves The Learning And Memory Ability Of Rats With Subarachnoid Hemorrhage

MWM results showed that on the 4th day after operation, the 3-day escape latency of rats after training was obviously prolonged in the SAH group (P < 0.01). The number of entries in target quadrant, the time spent in target quadrant markedly reduced in each SAH model group (P < 0.05). However, the SAH + G1 + HT group had an obvious shorter escape latency (P < 0.01), as well as an obvious larger number of entries in target quadrant and longer time spent in the target quadrant of each treatment group than the SAH group (P < 0.05). The number of entries in target quadrant and the time spent in target quadrant of the SAH + G1 + HT group was markedly raised relative to the SAH + G1 group and SAH + HT group (P < 0.05). Notably, there was no significant difference in average swimming speed among these groups (P > 0.05) (Fig. 2A-D).

On the 28th day after operation, the 3-day escape latency of rats after training significantly prolonged in the SAH group relative to the Sham group (P < 0.01). The number of entries in target quadrant and time spent in target quadrant markedly decreased in the SAH group relative to the Sham group (P < 0.05). Compared to the SAH group, the SAH + G1 + HT group exhibited an obvious decrease in escape latency (P < 0.01). A notable increase in the number of entries in target quadrant and time spent in target quadrant was found in each treatment group in comparison with the SAH group (P < 0.05). Likewise, there was no significant difference in average swimming speed among these groups (P > 0.05) (Fig. 2E-H).

G1 Combined With Hypothermia Improves The Learning And Memory Ability Of Rats With Subarachnoid Hemorrhage

NORT results showed that, on the 4th day after operation, rats in the Sham group spent observably more time on exploring TN than on TF (P < 0.01), and had much higher RI than other groups (P < 0.01). There was no significant difference between the time spent on exploring TN and on exploring TF by rats in the SAH group, the SAH + G1 group and the SAH + HT group. Rats in the SAH + G1 + HT group spent considerably more time on exploring TN than on TF (P < 0.01), but the time spent on exploring TN was less than the Sham group. Compared to that of the SAH group, RI of each treatment group was notably higher (P < 0.05). By the way, RI of the SAH + G1 + HT group was markedly higher than that of the SAH + G1 group and the SAH + HT group (P < 0.05) (Fig. 3A-B).

As for the 28th day after operation, rats in each group spent obviously more time on TN than on TF. However, the time rats in the SAH group spent on exploring TN was quite shorter than other groups, and the time rats in the SAH + G1 + HT group spent on exploring TN was longer than the SAH + G1 group and the SAH + HT group (P < 0.05). Compared to the Sham group, RI of rats in the SAH group declined significantly (P < 0.05), whereas compared to the SAH group, RI of each treatment group increased markedly (P < 0.05) (Fig. 3C-D).

G1 Combined With Hypothermia Reduces Anxiety- And Emotion-related Behavior Of Rats With Subarachnoid Hemorrhage

As revealed by the tests performed on the 4th day after operation, rats in each SAH model group showed a significant decline in the total travelled distance, time in the central zone, arm entries and total time spent in open arm of rats (P < 0.01); compared to the SAH group, the total travelled distance, time in the central zone, arm entries and total time spent in open arm of rats in each treatment group increased markedly (P < 0.01); and compared to the SAH + G1 group and the SAH + HT group, the total travelled distance, time in the central zone, arm entries and total time spent in open arm of the SAH + G1 + HT group were slightly higher, but no significant difference existed (P > 0.05) (Fig. 4A-D).

On the 28th day after operation, the total travelled distance, time in the central zone, arm entries and total time spent in open arm of SAH rats noticeably decreased relative to the Sham group (P < 0.01). Compared to the SAH group, the total travelled distance, time in the central zone, arm entries and total time spent in open arm of each treatment group markedly increased (P < 0.01). The SAH + G1 + HT group showed obviously higher total travelled distance, time in the central zone, arm entries and total time spent in open arm than the SAH + G1 group and the SAH + HT group (P < 0.01) (Fig. 4E-H).

G1 Combined With Hypothermia Enhances The Social Interaction Of Rats With Subarachnoid Hemorrhage

In order to assess the sociability of SAH rats, we carried out three-chamber paradigm test and reciprocal social interaction test. It was found that on the 4th day after operation, rats of the Sham group and the SAH + G1 + HT group spent obviously more time on S chamber than on E chamber (P < 0.01), but there was no significant difference between the time spent on S chamber than on E chamber of rats in the SAH, the SAH + G1 group and the SAH + HT group (P > 0.05); compared to the Sham group, the number of reciprocal social interaction bouts of SAH rats significantly declined (P < 0.01); compared to the SAH group, the number of reciprocal social interaction bouts of rats in each treatment group increased markedly (P < 0.05); the number of reciprocal social interaction bouts of rats in the SAH + G1 + HT group was obviously larger than the SAH + G1 group and the SAH + HT group (P < 0.05) (Fig. 5A-B).

On the 28th day after operation, the time spent on S chamber and the reciprocal social interaction bouts of rats in the SAH group were much less than the Sham group (P < 0.01). Nevertheless, those in each treatment group were markedly higher than SAH group (P < 0.01). The time spent on S chamber and the reciprocal social interaction bouts of rats in the SAH + G1 + HT group were slightly mounted relative to the SAH + G1 group and the SAH + HT group, but no significant difference was displayed between them (P > 0.05), as well as between the Sham group and the SAH + G1 + HT group (P > 0.05) (Fig. 5C-D).

SAH is a cerebral hemorrhage condition that seriously damages the brain and causes cognitive impairment (Mahmoud and Mason, 2015). Clinical emphasis has been directed toward saving the life and lowering the mortality and mutilation rate, but not toward the cognitive impairment after SAH(Cornea et al., 2022). Based on foreign relevant statistics, at least more than 60% of SAH patients has cognitive impairment at various degrees, involving impairment in multiple cognitive domains such as attention, memory, orientation, calculability, as well as analytical, comprehensive, judgement and executive abilities(Al-Khindi et al., 2010) Among them, memory, executive ability and language are most commonly involved. The cognitive impairment associated with these domains usually occurs within three months of onset and even lasts up to five or more years after onset(Proust et al., 2009), which poses tremendous difficulties in both work and life of the patient. Therefore, it is crucial to seek effective drugs or treatment that can alleviate cognitive impairment after SAH.

GPR30, a novel estrogen transmembrane receptor, can regulate rapid non-genomic estrogen signal transduction(Revankar et al.). It is mainly expressed in brain areas of the central nervous system such as hippocampus, cortex, striatum(Hammond and Gibbs, 2011). Previous studies showed that the neuroprotective effect of GPR30 agonist G1 on hippocampus and striatum before CA/CPR was similar to that of estrogen 2, indicating that this agonist has the dual effect of estrogen. Accordingly, activation of GPR30 has clinical value in the protecting brain tissue, and GPR30 also provides new ideas for estrogen replacement therapy in cerebral ischemia(Prossnitz et al., 2008). In addition, G1 can reduce the infarction size of hippocampus and striatum after cerebral ischemia(Kuiper et al., 1996). In a global brain ischemia model induced by vascular occlusion, G1 was demonstrated to reduce the neuronal mortality in the hippocampal CA1 region after cerebral ischemia and improve the cognitive impairment of neurons(Zhang et al., 2010). Our study revealed that Garcia scores of rats in all SAH model groups declined significantly on the 1st day after operation, and the cerebral edema degree decreased markedly, and increased gradually thereafter. However, the SAH + HT group, the SAH + G1 group and the SAH + G1 + HT group had higher recovery rates but lower cerebral edema degree than the SAH group. Garcia score and cerebral edema degree of the SAH + G1 + HT group were better than the SAH + HT group and the SAH + G1 group. The above suggested that G1 combined with hypothermia improved the neurological function of SAH rats and alleviated the cerebral edema degree. This finding is similar to the discoveries in previous studies. For instance, a study performed an intravenous injection of 300 µg/kg G1 one hour after SAH, and finally the neurological function of male rats was improved, which could be explained by the reduction of TUNEL/FJC positive neuronal mortality in the brain tissue of male rats with SAH. Although the combined treatment of G1 and hypothermia in this study shows a more pronounced intervention effect in SAH, further research into the mechanism of the combined treatment is still necessary.

A large number of literature studies suggested that those who have survived a SAH will have varying degrees of medium-long-term neurocognitive impairment, which is primarily manifested as impaired balance, memory and learning abilities, and impaired thought and expression(Turan et al., 2016). Multiple studies have demonstrated that MWM test possesses various advantages such as providing more experimental indexes to objectively reflect the rat’s learning and memory abilities of spatial orientation(Zhong et al., 2017); NORT is a non-aversion learning model depending on spontaneous exploration behavior of animals, which can detect the learning and memory abilities of animals(Okuda et al., 2004). Both MWM test and NORT were adopted in this study to evaluate the learning and memory abilities of SAH rats. The results suggested that on the 4th day and 28th day after operation, all SAH model groups with the longest escape latency had a significant decrease in the number of entries in target quadrant and the time spent in target quadrant of rats. However, compared to the SAH group, each treatment group with a lower escape latency, especially the SAH + G1 + HT group, remarkedly increased the number of entries in target quadrant and the time spent in target quadrant. It makes sense to assume that treatment of hypothermia alone or G1 treatment alone can improve the learning and memory ability of SAH rats, but more importantly, the combined treatment appears to have a slightly better effect. Moreover, the anxiety- and emotion-related behavior and social interaction of the rats were monitored using OFT, EPM test, three-chamber paradigm test and reciprocal social interaction test in this study. All test results demonstrated that compared to the SAH group the anxiety- and emotion- related behavior of rats was reduced and their social interaction enhanced obviously in all treatment groups, among which the SAH + G1 + HT group exhibited the strongest effect. It is speculated that this may be the result of the neuroprotective effect of G1 in the rats and the mitigative effect of hypothermia therapy in brain tissue injuries.

Collectively, G1 combined with hypothermia can improve the neurological function, lessen the cerebral edema degree, thereby alleviating cognitive impairment and anxiety-like behavior of SAH rats. The preliminary speculation of this result involves the respective functional effect of the two treatment. However, there are still some limitations in this study, like the lack of research into the mechanism of the combined treatment. Therefore, more exploration must be done on the detailed functional mechanism.

Author Contributions

Jun Peng: Writing – original draft, Writing – review & editing.

Yang He: Conceptualization, Methodology, Validation, Software,

Jun He: Investigation, Funding acquisition, Resources, Supervision.

Ji-kun Zhang: Investigation, Supervision.

Ying Xia: Writing – original draft, Writing – review & editing.

All authors given final approval of the version to be published.

Availability of Data and Materials

Data involved in the present work are available from corresponding author upon request.

Funding

This study was supported by Hainan Natural Science Foundation Youth Program (821QN422); Special Project of Hainan Cerebrovascular Disease Clinical Medical Research Center (LCYX202206).

Ethics approval

All experiments in this study were approved by Animal Ethics Committee of Haikou Affiliated Hospital of Central South University Xiangya School of Medicine (2022-200).

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Competing Interests

The authors declare that they have no competing interests.

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Reviewers agreed at journal
25 May, 2023
Reviewers invited by journal
17 Apr, 2023
Editor assigned by journal
12 Apr, 2023
First submitted to journal
09 Apr, 2023
Editorial decision: Minor Revisions Needed
07 Apr, 2023

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GPR30 Agonist G1 Combined with Hypothermia Alleviates Cognitive Impairment and Anxiety-like Behavior after Subarachnoid Hemorrhage in Rats

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Establishment and grouping of rat SAH model

Garcia Neurological Function Score

Determination Of Cerebral Edema Degree

Behavioral Tests Of Rats

Statistical analysis

Results

G1 Combined With Hypothermia Improves The Learning And Memory Ability Of Rats With Subarachnoid Hemorrhage

G1 Combined With Hypothermia Improves The Learning And Memory Ability Of Rats With Subarachnoid Hemorrhage

G1 Combined With Hypothermia Reduces Anxiety- And Emotion-related Behavior Of Rats With Subarachnoid Hemorrhage

G1 Combined With Hypothermia Enhances The Social Interaction Of Rats With Subarachnoid Hemorrhage

Discussion

Conclusion

Declarations

References

Status:

Version 1