Table 1.

Synthesis of included studies [25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41].

Scheme 1.	Aim	Animal Model/Cell Line	Methods	Results
1. Basalay et al. 2019 [25]	-Examine the Neuroprotective Effects of liraglutide And semaglutide	Male nondiabetic Sprague-Dawley rats	-A model of acute ischemic stroke (middle cerebral artery occlusion) was used to assess the effects of liraglutide or semaglutide administered i.v. at onset or s.c. before it. -Infarct size and functional status were evaluated after 24 or 72 h of reperfusion.	-Liraglutide reduced brain damage dose-dependent. -Reperfusion delay is a limiting factor For neuroprotection by liraglutide. -Neuroprotection by semaglutide is at least as potent as by liraglutide. -The principal clinic-related difference between semaglutide and liraglutide is the substantially longer half-life.
2. Chen et al. 2023 [26]	-Investigate differences in cognitive function and hippocampal phosphorylated protein expression in high-fat diet-induced obese mice after treatment with semaglutide and empagliflozin.	C57BL/6JC male mice	-Control (C) and high-fat diet (H) -After 12 weeks, Group H Was divided into: -Group H -Group semaglutide: Intraperitoneal injections of 30 nmol/kg/d bodyweight of Semaglutide for 12 weeks -Group empagliflozin: gavage administration of 10 mg/kg/d bodyweight of empagliflozin for 12 weeks -Groups C and H received equal volumes of saline via the same routes.	-The use of semaglutide treatment decreased escape latency and Increased the total percentage of time spent swimming. -Semaglutide and empagliflozin increased the phosphorylation of CACNA1D, CACNA1A, and CACNA1B proteins.
3. Wang et al. 2021 [27]	-Investigate the functions of semaglutide in epilepsy and inflammation models	C57BL/6J mice	-In vitro: inflammation model Using lipopolysaccharide (LPS) and nigericin stimulation in BV2 cells. -In vivo: chronic epilepsy model using a pentylenetetrazole (PTZ) kindling method.	-Semaglutide decreased inflammation and reduced cell damage by blocking NLRP3 inflammasome activation in BV2 cells treated with LPS and nigericin. -Semaglutide reduced seizure severity, prevented hippocampal neuron death, improved cognition, blocked NLRP3 inflammasome activation, and lowered inflammatory cytokine levels.
4. M.A. Sadek et al. 2023 [28]	-Investigate the Influence of semaglutide on experimental autoimmune encephalomyelitis (EAE)-induced multiple sclerosis (MS) in mice.	Adult male Swiss albino mice	-The standard control group received saline (0.2 ml; intraperitoneal [i.p.]). -The semaglutide-control group received semaglutide (25 nmol/kg/day; i.p.) -The EAE group was subjected to EAE induction and treated with saline (0.2 ml; i.p.). -The semaglutide-treated group was subjected to EAE induction and treated with semaglutide (25 nmol/kg/day i.p.) Two hours after EAE induction. -All treatments were administered for two weeks starting from EAE induction.	-Semaglutide: reduced EAE-induced clinical signs -Mitigates EAE-induced weight changes in CNS organs -Attenuated EAE-induced motor impairment, cognitive dysfunction -Amended EAE-induced histological alterations in the corpus callosum and brain atrophy and demyelination -Lessened EAE-induced oxidative stress and neuroinflammation
5. Zhang Q. et al. 2022 [29]	-Explore the effect of A1 astrocytes on BBB integrity after ischemic stroke	Adult male ICR mice	-Transient middle cerebral artery occlusion (TMCAO). -Immunohistochemical staining of A1 (c3d) and A2 (S100A10) were performed to characterize astrocyte phenotypic changes after TMCAO. -Intraperitoneal injection with semaglutide to inhibit A1 astrocytes.	-The number of c3d+/GFAP+ A1 astrocytes increased within 14 days after S100A10+/GFAP+ TMCAO, while A2 astrocytes decreased. -Treatment with semaglutide decreased the count of microglia expressing CD16/32 and astrocytes expressing C3d and GFAP, which are characteristic of A1 astrocytes. -Semaglutide reduced brain infarct volume and neuroinflammation; improved neurobehavioral outcomes.
6. Chen et al. 2023 [30]	-Investigate the effects of semaglutide on phosphorylated protein expression and its neuroprotective mechanism in hippocampi of high-fat-diet- induced obese mice	C57BL/6J male normal mice	-Control group (c) regular diet -Model group (H) high-fat diet + saline -Semaglutide group (H+ semaglutide, group S) semaglutida 30 nmol/kg/d for 12 weeks -Morris water maze assay to detect cognitive function changes -Phosphorylated proteomic analysis to detect the hippocampal protein profile in mice	Semaglutide intervention on high-fat diet-induced obese mice: -reduced body weight -improved oxidative stress indexes -shortened the water maze platform latency -Semaglutide reduces phosphorylation and increases neuroprotection in obese mice.
7. Z.J. Wang et al. 2023 [31]	-Correlate the GLP-1R/SIRT1/GLUT4 pathway with glucose metabolism. -Investigate the mechanism of action For improving glucose metabolism in the 3xtg transgenic mouse model of Alzheimer’s disease and cultured neurons.	-male APP/PS1/Tau transgenic mice (3xtg) -C57B6/129 wild-type mice (WT)	-WT + saline group -3xtg + saline group -3xtg + semaglutida group -3xtg + semaglutide + EX527 (SIRT1 inhibitor) group -15 mice in each group were injected with semaglutide (0.1 mg/kg, i.p.) or saline (0.9%, i.p.) every other day for 30 days before the behavioral experiment.	Semaglutide increased the expression levels of SIRT1 and GLUT4 in the hippocampus of 3xtg mice, → improved learning and memory, and decreased Aβ plaques and neurofibrillary tangles. -Improved glucose metabolism, promoted glycolysis, and improved glycolytic disorders -Increased the membrane translocation of GLUT4 in cultured HT22 cells.
8. Liu et al. 2022 [40]	-Explore the neuroprotective effects of semaglutide in PD -Compared the effect of semaglutide with liraglutide at the same dose	-SH-SY5Y The cell line of human neuroblastoma	-Treated the human neuroblastoma SH-SY5Y the cell line with 6-hydroxydopamine (6-OHDA) as a PD in vitro model	-Semaglutide and liraglutide protect against 6-OHDA cytotoxicity by increasing autophagy flux and decreasing oxidative stress and mitochondrial dysfunction in SH-SY5Y cells. -Semaglutide was superior to liraglutide for most parameters measured
9. L. Zhang et al. 2018 [32]	-Report the protective effects of semaglutide (25 nmol/kg ip, once daily for seven days) in the MPTP mouse model of PD. -Compare the neuroprotective effects of semaglutide and liraglutide when given at the exact dosage.	-Male C57BL/6 Mice	-Control group treated with saline -Liraglutide group treated with saline and liraglutide -Semaglutide group treated with saline and semaglutide -MPTP group treated with MPTP -MPTP (once daily 20 mg/kg i.p. for seven days) followed immediately by liraglutide-treated group (25 nmol/kg i.p. once daily for seven days) -MPTP (20 mg/kg i.p. once daily for seven days) followed immediately by semaglutide-treated group (25 nmol/kg i.p. once daily for seven days).	-Semaglutide and liraglutide were found to have improved the motor impairments caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). -Semaglutide was found to be better than liraglutide in most of the measurements taken.
10. L. Zhang et al. 2019 [33]	-Investigate the neuroprotective effects of semaglutide (25 nmol/kg i.p. once every two days for 30 days) and liraglutide (25 nmol/kg i.p. once daily for 30 days) in the chronic MPTP mouse model of PD.	-Male C57BL/6 Mice	-Control group treated with saline -Liraglutide group (25 nmol/kg i.p. once daily for 30 days) -Semaglutide group (25 nmol/kg i.p. once every two days for 30 days) -MPTP group treated with MPTP alone (once daily 20 mg/kg i.p. for 30 days) -MPTP (once daily 20 mg/kg i.p. for 30 days) + liraglutide-treated group (25 nmol/kg i.p. once daily for 30 days) -MPTP (20 mg/kg i.p. once daily for 30 days) + semaglutide-treated group (25 nmol/kg i.p. once every two days for 30 days).	MPTP-induced increase in alfa-syn expression in the brain is reduced by semaglutide and liraglutide. Semaglutide is more potent than once daily liraglutide in most parameters measured.
11. L. Zhang et al. 2022 [34]	-Developed a dual GLP-1/GIP receptor agonist (DA5-CH) that can cross the blood-brain barrier at a higher rate than semaglutide. -Tested semaglutide and DA5-CH in the 6-OHDA-lesion rat model of PD	-Adult male Sprague-Dawley (SD) rats	-Stereotactic surgery -A sham + saline group -A 6-OHDA+ saline group -A 6-OHDA+ semaglutide group -A 6-OHDA+DA5-CH group -Treatment was semaglutide or DA5-CH (25 nmol/kg, i.p.) daily for 30 days postlesion.	-Both drugs protected dopaminergic neurons and increased TH expression in the substantia nigra. -The level of monomer and aggregated α-synuclein was reduced.
12. X. Yang et al. 2019 [35]	-Providing new insight into the semaglutide neuroprotective effects in the rat brain	-Adult male Sprague –Dawley	-Permanent middle cerebral artery occlusion (PMCAO) model -Sham-operated group -Vehicle control group -Semaglutide group—2 h after MCAO intraperitoneally (10 nmol/kg), -Injected every second day for 1, 7, 14, and 21 days -Tissue sampling after 21 days of observation	-After ischemia, semaglutide treatment improved the functional recovery of rats without affecting blood glucose levels. -The drug reduced inflammation and apoptosis and normalized cell growth signaling and neurogenesis.
13. Poupon- Bejuit et al. 2022 [36]	-Evaluate the therapeutic efficacy of semaglutide in a mouse model of INAD (infantile neuroaxonal dystrophy)	-Pla2g6−/− mice	-In this study, a mouse model with the Pla2g6 knock-in was given semaglutide at three different doses through intraperitoneal injection once a week. The treatment began when the mice were three weeks old, and their survival was monitored and compared to age-matched untreated Pla2g6−/− mice and wild-type mice (WT), which were used as controls.	-Weekly delivery of high-dose semaglutide improved lifespan and locomotor function in juvenile INAD mice. Semaglutide has been shown to increase the levels of molecules that protect the brain while simultaneously decreasing those molecules that promote neurodegeneration. -The expression of mediators in the apoptotic and necroptotic pathways was significantly reduced in mice treated with semaglutide.
14. T.S. Salameh et al. 2020 [37]	-Compare the pharmacokinetics of 125I-labeled single IRAs (exendin-4, liraglutide, lixisenatide, semaglutide) and 125I-labeled dual IRAs	-Male CD-1 mice	-Consequently, compared brain uptake pharmacokinetics of intravenous 125I-labeled IRAs in adult CD-1 mice over 60 min	-The nonacylated and nonpegylated IRAs (exendin-4, lixisenatide, Peptide 17, DA3-CH, and DA-JC4) had significant rates of blood-to-brain influx (Ki). -The acylated IRAs (liraglutide, semaglutide, and Peptide 18) did not measurably cross the BBB. The capillaries completely segregated semaglutide and Peptide 18, and none of the 125I-semaglutide or Peptide 18 was found in the brain tissue.
15. Yan-fang Chang et al. 2020 [41]	-Explore the potential mechanisms of semaglutide against AD	-SH-SY5Y cells	-SH-SY5Y cells damaged by Ab25–35 were treated by semaglutide. -Autophagy-related proteins and apoptosis-related proteins were measured to explore molecular mechanisms.	-Semaglutide inhibited apoptosis and increased the expression of Bcl2 inhibited by Ab25–35. -Semaglutide activity in preventing SH-SY5Y cells against Ab25–35 present a potential mechanism for enhancing autophagy and inhibiting apoptosis.
16. Thornton et al. 2024 [38]	-Identify specific NLRP3-sensitive mechanismscontributing to obesity-induced inflammation -Compare an NLRP3 inhibitor to semaglutide to evaluate its association with systemic inflammatory response, and cerebral gliosis	-Male C57BL/6J mice	-To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, two different clinical-stage NLRP3 inflammasome inhibitors were tested. -After being on a high-fat diet for 15 weeks, mice induced with diet-induced obesity (DIO) weighed significantly more than the mice fed a regular chow-based diet. To understand the effect of the LRP3 inhibitor NT-0249, it was compared with semaglutide or calorie restriction for an additional 28 days.	-NLRP3 inhibitors can block the cellular inflammatory response to obesity-related molecular patterns. -In pre-existing obese states in mice, inhibiting NLRP3 can reduce systemic inflammation and astrogliosis. When dosed to achieve brain exposure, NLRP3 inhibitors can reverse pre-established obesity at a similar efficacy to the GLP-1RA semaglutide.
17. Shnaien et al. 2023 [39]	-Examine the neuroprotective effects of semaglutide during endotoxemia and its role in modulating pro-inflammatory mediators.	-Adult male Swiss albino mice	-Laparotomy without/with cecal ligation and puncture (CLP) -Semaglutide administration before CLP -Sham group: laparotomy surgery without CLP. -CLP group: (sepsis group) •Vehicle group: mice were given an equal volume of distilled water (DW) by subcutaneous injection Daily for seven days before CLP. •Semaglutide group: mice received 40 µg/kg of semaglutide	-The brain tissue level of TLR4\STAT3 of the semaglutide-treated group was significantly lower. -The brain tissues obtained from mice treated with semaglutide showed significantly less cellular injury. -Semaglutide can protect against sepsis and prevent brain dysfunction.