Neuromodulation Induced by Sitagliptin: A New Strategy for Treating Diabetic Retinopathy

Diabetic retinopathy (DR) involves progressive neurovascular degeneration of the retina. Reduction in synaptic protein expression has been observed in retinas from several diabetic animal models and human retinas. We previously reported that the topical administration (eye drops) of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, prevented retinal neurodegeneration induced by diabetes in db/db mice. The aim of the present study is to examine whether the modulation of presynaptic proteins is a mechanism involved in the neuroprotective effect of sitagliptin. For this purpose, 12 db/db mice, aged 12 weeks, received a topical administration of sitagliptin (5 μL; concentration: 10 mg/mL) twice per day for 2 weeks, while other 12 db/db mice were treated with vehicle (5 μL). Twelve non-diabetic mice (db/+) were used as a control group. Protein levels were assessed by western blot and immunohistochemistry (IHC), and mRNA levels were evaluated by reverse transcription polymerase chain reaction (RT-PCR). Our results revealed a downregulation (protein and mRNA levels) of several presynaptic proteins such as synapsin I (Syn1), synaptophysin (Syp), synaptotagmin (Syt1), syntaxin 1A (Stx1a), vesicle-associated membrane protein 2 (Vamp2), and synaptosomal-associated protein of 25 kDa (Snap25) in diabetic mice treated with vehicle in comparison with non-diabetic mice. These proteins are involved in vesicle biogenesis, mobilization and docking, membrane fusion and recycling, and synaptic neurotransmission. Sitagliptin was able to significantly prevent the downregulation of all these proteins. We conclude that sitagliptin exerts beneficial effects in the retinas of db/db mice by preventing the downregulation of crucial presynaptic proteins. These neuroprotective effects open a new avenue for treating DR as well other retinal diseases in which neurodegeneration/synaptic abnormalities play a relevant role.

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New Insights into the Mechanisms of Action of Topical Administration of GLP-1 in an Experimental Model of Diabetic Retinopathy

Journal of Clinical Medicine ◽

10.3390/jcm8030339 ◽

2019 ◽

Vol 8 (3) ◽

pp. 339 ◽

Cited By ~ 10

Author(s):

Joel Sampedro ◽

Patricia Bogdanov ◽

Hugo Ramos ◽

Cristina Solà-Adell ◽

Mireia Turch ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Neurovascular Unit ◽

Topical Administration ◽

Inflammatory Factors ◽

Eye Drops ◽

Beneficial Effects ◽

Apoptotic Protein ◽

Glucagon Like Peptide 1 ◽

Underlying Mechanisms

The main goals of this work were to assess whether the topical administration of glucagon-like peptide-1 (GLP-1) could revert the impairment of the neurovascular unit induced by long-term diabetes (24 weeks) in diabetic mice and to look into the underlying mechanisms. For that reason, db/db mice were treated with eye drops of GLP-1 or vehicle for 3 weeks. Moreover, db/+ mice were used as control. Studies performed in vivo included electroretinogramand the assessment of vascular leakage by using Evans Blue. NF-κB, GFAP and Ki67 proteins were analyzed by immunofluorescence (IF). Additionally, caspase 9, AMPK, IKBα, NF-κB, AKT, GSK3, β-catenin, Bcl-xl, and VEGF were analyzed by WB. Finally, VEGF, IL-1β, IL-6, TNF-α, IL-18, and NLRP3 were studied by reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence. We found that topical administration of GLP-1 reverted reactive gliosis and albumin extravasation, and protected against apoptosis and retinal dysfunction. Regarding the involved mechanisms, GLP-1 exerted an anti-inflammatory action by decreasing NF-κB, inflammosome, and pro-inflammatory factors. In addition, it also decreased VEGF expression. Furthermore, GLP-1 promoted cell survival by increasing the anti-apoptotic protein Bcl-xl and the signaling pathway Akt/GSK3b/β-catenin. Finally, Ki67 results revealed that GLP-1 treatment could induce neurogenesis. In conclusion, the topical administration of GLP-1 reverts the impairment of the neurovascular unit by modulating essential pathways involved in the development of diabetic retinopathy (DR). These beneficial effects on the neurovascular unit could pave the way for clinical trials addressed to confirm the effectiveness of GLP-1 in early stages of DR.

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Fasudil attenuates Neuro-Inflammation and Oxidative Stress via Rhoa/Rock Pathways in Delayed Neuropsychologic Sequelae Mice Model

10.21203/rs.3.rs-1055014/v1 ◽

2021 ◽

Author(s):

Xiang Yan ◽

Meng Fu ◽

Ye Gao ◽

Qin Han ◽

Shuang Li ◽

...

Keyword(s):

Oxidative Stress ◽

Neuroprotective Effect ◽

Carbon Monoxide Poisoning ◽

Immunofluorescence Staining ◽

Control Group ◽

Spatial Learning And Memory ◽

Mrna Levels ◽

Co Poisoning ◽

Mice Model ◽

Tnf Α

Abstract Background Delayed neuropsychologic sequelae is common in patients after carbon monoxide poisoning without effective methods worldwide. Fasudil exerts neuroprotective effect and alleviates oxidative stress in some neurodegenerative disorders. However, the mechanism between DNS and FS remains unclear. The study aims to explore the efficacy and mechanism of Fasudil in DNS mice model. Objective The delayed neuropsychologic sequelae model was induced with a hyperbaric oxygen chamber. All rats were randomly assigned to three groups (n=10): air control group (AC), CO poisoning group (CO), and CO poisoning +Fasudil group (CO+FS). Rats in the CO+FS group were given Fasudil (10 mg/kg/day, ip). The morris water maze was documented to estimate spatial learning and memory of mice. The demyelination state in brain was observed through LFB staining. The protein of MBP was examined with immunofluorescence staining. The levels of IL-6, TNF-α, TGF-β, SOD, and MDA were examined by ELISA. The mRNA levels of Rho, ROCK2, MLC1 and MYPT1 were analyzed by rt-PCR. Result The cognitive impairment in the CO+FS group were significantly reduced than those of the CO group (P<0.05). LFB staining and immunofluorescence staining of MBP results showed that FS significantly treatment attenuated demyelination (P<0.05). Compared with the CO group, the levels of TNF-α, IL-6, MDA, ROCK2, MLC1, and MYPT1 significantly decreased (P<0.05), and the levels of SOD were significantly increased in the CO+FS group (P<0.05). Conclusion In a word, Fasudil attenuated delayed neuropsychologic sequelae by inhibiting inflammation, oxidative stress and downregulating Rho/ROCK pathway in DNS mice model. We conclude that Fasudil may be a novel treatment for delayed neuropsychologic sequelae.

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Hyperpolarized [1-13C]lactate flux increased in the hippocampal region in diabetic mice

Molecular Brain ◽

10.1186/s13041-019-0505-9 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Young-Suk Choi ◽

Jae Eun Song ◽

Jong Eun Lee ◽

Eosu Kim ◽

Chul Hoon Kim ◽

...

Keyword(s):

Active Form ◽

Lactate Production ◽

Fold Increase ◽

Serum Glucose ◽

Control Group ◽

Resonance Spectroscopy ◽

Mrna Levels ◽

Diabetic Mice ◽

Hippocampal Region ◽

Atp Citrate Lyase

Abstract Increasing evidence suggests there is a relationship between cognitive impairment and metabolic dysfunction. Diabetes is a chronic disease, and metabolic factors affecting brain metabolisms, such as serum glucose, insulin, and glucagon, are altered according to disease progression. In our previous study, we applied hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy in prediabetic mice after feeding them a 60% high-fat diet (HFD) for 6 months. Ultimately, we detected significantly increased [1-13C]lactate conversion in the whole brain and an almost five-fold increased [1-13C]lactate/pyruvate ratio in the hippocampal region. In the present study, we induced diabetes in mice by injecting streptozotocin and feeding them an HFD for 6 months. Unlike in prediabetic mice, [1-13C]lactate conversion in the diabetic mice did not differ from that in the control group, but [1-13C]lactate/total 13C ratio showed an almost 1.4-fold increase in the hippocampal region. We measured the amount of the lactate and mRNA levels of glucose transporters from isolated hippocampus and cortex samples. In the hippocampus, significantly decreased GLUT1 mRNA levels and increased lactate were detected, suggesting an inconsistency between glucose and pyruvate metabolism. Pyruvate can be produced from oxaloacetate as well as glucose. We investigated ATP citrate lyase (ACLY) because it cleaves citrate into oxaloacetate and acetyl CoA. Phosphorylated ACLY (Ser455), the active form, was increased in both hippocampus and cortex samples of mice injected with streptozotocin and fed an HFD. Also, phosphorylated ACLY/total ACLY showed a positive correlation with lactate amount in the hippocampus. Our results suggest that the brain has different responses to diabetic progression, but, in the hippocampus, maintains metabolic alteration toward increasing lactate production from the prediabetic to the diabetic stage. We suggest that ACLY-mediated pyruvate be used to support lactate levels in the hippocampus in cases of limited glucose availability.

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A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00475.2009 ◽

2009 ◽

Vol 297 (6) ◽

pp. E1276-E1282 ◽

Cited By ~ 24

Author(s):

Long Cheng ◽

Xiao Han ◽

Yuguang Shi

Keyword(s):

Diabetic Retinopathy ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Regulatory Role ◽

Mrna Levels ◽

Diabetic Mice ◽

Acyltransferase Activity ◽

Onset Of Diabetes ◽

Anti Inflammatory

Platelet-activating factor (PAF) and lysophosphatidylcholine (LPC) are potent inflammatory lipids. Elevated levels of PAF and LPC are associated with the onset of diabetic retinopathy and neurodegeneration. However, the molecular mechanisms underlying such defects remain elusive. LPCAT1 is a newly reported lysophospholipid acyltransferase implicated in the anti-inflammatory response by its role in conversion of LPC to PC. Intriguingly, the LPCAT1 enzyme also catalyzes the synthesis of PAF from lyso-PAF with use of acetyl-CoA as a substrate. The present studies investigated regulatory roles of LPCAT1 in the synthesis of inflammatory lipids during the onset of diabetes. Our work shows that LPCAT1 plays an important role in the inactivation of PAF by catalyzing the synthesis of alkyl-PC, an inactivated form of PAF with use of acyl-CoA and lyso-PAF as substrates. In support of a role of LPCAT1 in anti-inflammatory responses in diabetic retinopathy, LPCAT1 is most abundantly expressed in the retina. Moreover, LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain tissues in response to the onset of diabetes in Ins2 Akita and db/db mice, mouse models of type 1 and type 2 diabetes, respectively. Conversely, treatment of db/db mice with rosiglitazone, an antidiabetes compound, significantly upregulated LPCAT1 mRNA levels concurrently with increased acyltransferase activity in the retina and brain. Collectively, these findings identified a novel regulatory role of LPCAT1 in catalyzing the inactivation of inflammatory lipids in the retina of diabetic mice.

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Dexmedetomidine post-conditioning attenuates cerebral ischemia following asphyxia cardiac arrest through down-regulation of apoptosis and neuroinflammation in rats

BMC Anesthesiology ◽

10.1186/s12871-021-01394-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Guangqian Li ◽

LeiQian ◽

Pan Gu ◽

Dan Fan

Keyword(s):

Cardiac Arrest ◽

Neuroprotective Effect ◽

Serum Levels ◽

Spontaneous Circulation ◽

Cerebral Injury ◽

Control Group ◽

Tunel Staining ◽

Apoptotic Cells ◽

Neuroprotective Effects ◽

Return Of Spontaneous Circulation

Abstract Background Neuroprotection strategies after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR) remain key areas of basic and clinical research. This study was designed to investigate the neuroprotective effects of dexmedetomidine following resuscitation and potential mechanisms. Methods Anesthetized rats underwent 6-min asphyxia-based cardiac arrest and resuscitation, after which the experimental group received a single intravenous dose of dexmedetomidine (25 μg/kg). Neurological outcomes and ataxia were assessed after the return of spontaneous circulation. The serum levels and brain expression of inflammation markers was examined, and apoptotic cells were quantified by TUNEL staining. Results Neuroprotection was enhanced by dexmedetomidine post-conditioning after the return of spontaneous circulation. This enhancement was characterized by the promotion of neurological function scores and coordination. In addition, dexmedetomidine post-conditioning attenuated the serum levels of the pro-inflammatory cytokine tumor necrosis factor (TNF)-α at 2 h, as well as interleukin IL-1β at 2, 24, and 48 h. TUNEL staining showed that the number of apoptotic cells in the dexmedetomidine post-conditioning group was significantly reduced compared with the control group. Further western blot analysis indicated that dexmedetomidine markedly reduced the levels of caspase-3 and nuclear factor-kappa B (NF-κB) in the brain. Conclusions Dexmedetomidine post-conditioning had a neuroprotective effect against cerebral injury following asphyxia-induced cardiac arrest. The mechanism was associated with the downregulation of apoptosis and neuroinflammation.

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NEUROPROTECTIVE EFFECTS OF POMEGRANATE JUICE ON LEAD INDUCED NEUROTOXICITY IN MICE

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2017v9i2.15806 ◽

2017 ◽

Vol 9 (2) ◽

pp. 207

Author(s):

Leila Gadouche ◽

Noureddine Djebli ◽

Khayra Zerrouki

Keyword(s):

Drinking Water ◽

Cerebral Cortex ◽

Lead Acetate ◽

Neuronal Degeneration ◽

Neuroprotective Effect ◽

Pomegranate Juice ◽

Total Phenolic ◽

Control Group ◽

Histological Structure ◽

Neuroprotective Effects

Objective: This study evaluates the potential neuroprotective of the pomegranate juice against chronic intoxication with lead acetate for 3 months.Methods: Twenty-one female Swiss mice divided into 3 groups were employed in the present investigation. Control group: received drinking water for 90 days, neurotoxic group were exposed to 1000 ppm of lead acetate in the drinking water for 12 weeks, and neurotoxic treated group represents the mice received treatment with juice pomegranate diluted with distilled water (v/v) orally for 4 h / day followed by lead acetate at a dose of 1000 ppm orally for 20 h / day for 90 days. After cessation of treatment, neurobehavioral studies using the open field test, black and white test box and swimming test were made. In the next phase, brain injury was assessed histologically with hematoxylin-eosin staining.Results: Chronic exposure to lead led to significant increase in the level of anxiety, depression and the locomotor activity (P < 0.05). It was confirmed by histopathological alterations in many areas of the cerebral cortex and hippocampus including neuronal degeneration and decrease cell density. Treatment with the juice significantly improve the level of depression, locomotor function (P < 005) and anxiety (P > 0.05) in mice exposed to lead as well as restored the histological structure in cerebral cortex and hippocampus of mice. The total phenolic and flavonoids content in juice of pomegranate was found to be 3809. 8±29.404 mg GAE/l; 2109. 57±18.936 mg QE /l of juice.Conclusion: This finding suggests that phenolic compounds found in pomegranate juice provide a neuroprotective effect on behavioural impairments and histopathological change induced by lead.

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Shenzhi Jiannao formula ameliorates vascular dementia in vivo and in vitro by inhibition glutamate neurotoxicity via promoting clathrin-mediated endocytosis

Chinese Medicine ◽

10.1186/s13020-021-00477-4 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Danfeng Tian ◽

Yangyang Guo ◽

Dandan Zhang ◽

Qiang Gao ◽

Ganlu Liu ◽

...

Keyword(s):

Cell Death ◽

Vascular Dementia ◽

Pc12 Cells ◽

Neuroprotective Effect ◽

Glutamate Excitotoxicity ◽

Mrna Levels ◽

Neuroprotective Effects ◽

Promising Alternative

Abstract Background Synaptic damage and glutamate excitotoxicity have been implicated in the pathogenesis of vascular dementia (VD). Clathrin, RAB5B and N-methyl-d-aspartic acid receptor 1 (NMDAR1) proteins play a vital role in endocytosis of synaptic vesicles in neurons and glutamate over accumulation. Previous researches have been confirmed that Shenzhi Jiannao (SZJN) formula has an anti-apoptotic and neuroprotective effect in VD, but the underlying mechanisms are still unclear. In this study, we aimed to explore the effect of SZJN formula on cognitive impairment and glutamate excitotoxicity via clathrin-mediated endocytosis (CME) in vivo and in vitro. Methods SZJN formula consists of Panax ginseng C.A.Mey., Anemarrhena asphodeloides Bunge, and Paeonia anomala subsp. veitchii (Lynch) D.Y.Hong & K.Y.Pan. All herbs were prepared into granules. Both common carotid arteries were permanent occluded (2‐vessel occlusion, 2VO) in male Sprague Dawley (SD) rats to model VD. One day after operation, the rats began daily treatment with SZJN formula for 2 weeks. The neuroprotective effects of SZJN formula was subsequently assessed by the novel object recognition test, Morris water maze, hematoxylin–eosin (HE) staining and Nissl staining. Glutamate cytotoxicity was assessed by detecting cell viability and cell death of PC12 cells. Immunohistochemistry, immunofluorescence, Western blot, and quantitative real‐time PCR were used to detect the expression levels of clathrin, RAB5B, and NMDAR1. Results Administration of SZJN formula effectively improved short-term memory and spatial memory. SZJN formula treatment significantly reduced hippocampal neuronal loss, and recovered the arrangement and morphology of neurons and Nissl bodies. Moreover, SZJN formula promoted the proliferation of PC12 cells and inhibited glutamate-induced cell death. The down-regulation of clathrin and RAB5B, as well as the upregulation of NMDAR1 in the brain induced by 2VO or glutamate was also notably reversed by SZJN formula at both the protein and mRNA levels, which may contribute to SZJN formula induced improved neurological function. Conclusions Taken together, our findings provide evidence that the neuroprotective effects of SZJN formula in experimental VD maybe mediated through promoting the expression of clathrin-mediated endocytosis and reducing NMDARs‐associated glutamate excitotoxicity. SZJN formula serves as a promising alternative therapy and may be a useful herbal medicine for preventing progression of VD. Graphic abstract

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Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.718902 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carlo Gesualdo ◽

Cornel Balta ◽

Chiara Bianca Maria Platania ◽

Maria Consiglia Trotta ◽

Hildegard Herman ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Diabetic Retinopathy ◽

Growth Factor ◽

Drug Repurposing ◽

Melanocortin Receptors ◽

Control Group ◽

Vascular Endothelial ◽

Diabetic Mice ◽

Dynamic Simulations ◽

Endothelial Growth Factor

This study aimed to investigate the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 (MCR1, MCR5). In particular, we investigated the effects of fingolimod, a drug approved to treat relapsing-remitting multiple sclerosis, on retinal angiogenesis in a mouse model of diabetic retinopathy (DR). We showed, by a molecular modeling approach, that fingolimod can bind with good-predicted affinity to MC1R and MC5R. Thereafter, we investigated the fingolimod actions on retinal MC1Rs/MC5Rs in C57BL/6J mice. Diabetes was induced in C57BL/6J mice through streptozotocin injection. Diabetic and control C57BL/6J mice received fingolimod, by oral route, for 12 weeks and a monthly intravitreally injection of MC1R antagonist (AGRP), MC5R antagonist (PG20N), and the selective S1PR1 antagonist (Ex 26). Diabetic animals treated with fingolimod showed a decrease of retinal vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), compared to diabetic control group. Fingolimod co-treatment with MC1R and MC5R selective antagonists significantly (p < 0.05) increased retinal VEGFR1, VEGFR2, and VEGFA levels compared to mice treated with fingolimod alone. Diabetic animals treated with fingolimod plus Ex 26 (S1PR1 selective blocker) had VEGFR1, VEGFR2, and VEGFA levels between diabetic mice group and the group of diabetic mice treated with fingolimod alone. This vascular protective effect of fingolimod, through activation of MC1R and MC5R, was evidenced also by fluorescein angiography in mice. Finally, molecular dynamic simulations showed a strong similarity between fingolimod and the MC1R agonist BMS-470539. In conclusion, the anti-angiogenic activity exerted by fingolimod in DR seems to be mediated not only through S1P1R, but also by melanocortin receptors.

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Neuroprotective Effect of Chronic Intracranial Toxoplasma gondii Infection in a Mouse Cerebral Ischemia Model

The Korean Journal of Parasitology ◽

10.3347/kjp.2020.58.4.461 ◽

2020 ◽

Vol 58 (4) ◽

pp. 461-466

Author(s):

Seung Hak Lee ◽

Bong-Kwang Jung ◽

Hyemi Song ◽

Han Gil Seo ◽

Jong-Yil Chai ◽

...

Keyword(s):

Cerebral Ischemia ◽

Toxoplasma Gondii ◽

Neuroprotective Effect ◽

Hypoxia Inducible Factor ◽

Protozoan Parasite ◽

Artery Occlusion ◽

Control Group ◽

Triphenyltetrazolium Chloride ◽

Neuroprotective Effects ◽

Neurobehavioral Function

Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.

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Neuroprotective Effects of Purple Sweet Potato Balinese Cultivar in Wistar Rats With Ischemic Stroke

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.435 ◽

2018 ◽

Vol 6 (11) ◽

pp. 1959-1964 ◽

Cited By ~ 2

Author(s):

I Made Oka Adnyana ◽

AA Raka Sudewi ◽

DPG Purwa Samatra ◽

DN Suprapta

Keyword(s):

Ischemic Stroke ◽

Cytochrome C ◽

Sweet Potato ◽

Ipomoea Batatas ◽

Caspase 3 ◽

Neuroprotective Effect ◽

Control Group ◽

Neuroprotective Effects ◽

Apoptosis Rate ◽

Purple Sweet Potato

BACKGROUND: Purple sweet potato (Ipomoea Batatas L.) is one of the sources for anthocyanin, which promotes the health through antioxidant, anti-inflammatory, anti-cancer, neuroprotection, and anti-apoptosis activities. Oxidative stress has been shown to be the cause of apoptosis in ischemic stroke. AIM: The objective of this research was to delineate the pleiotropic effects of anthocyanin for neuroprotection during an acute stroke event. METHODS: Anthocyanin was extracted from Balinese cultivar of purple sweet potato and subsequently administered to rat models of induced ischemic stroke (labelled as treatment group), as well as a placebo (labelled as a control group). Several parameters were in turn evaluated, i.e. the activities of anti-apoptotic (Bcl-2) as well as pro-apoptotic (cytochrome c, caspase-3) molecules, and apoptosis rate. Bcl-2 levels were determined using the histochemical method, cytochrome c and caspase-3 via ELISA method, while apoptosis rate was measured by TdT-medicated Dutp-Nick End Labeling (TUNEL) assay. RESULTS: Bcl-2 expression demonstrated significantly higher Bcl-2 expression in the treatment compared with control group (median 31.2 vs. 1.1; p = 0.001). Accordingly, pro-apoptotic cytochrome c and caspase-3 levels were also found significantly lower in the treatment as opposed to control group (mean 4.17 vs. 8.06; p = 0.001; mean 3.81 vs. 8.02; p = 0.001). Ultimately, apoptosis rate was found markedly lower among treatment than control groups (mean 3.81 vs. control 21.97; p = 0.003). CONCLUSION: The results of this study indicated a significant neuroprotective effect of anthocyanin derived from Balinese cultivar of PSP. Anthocyanin was able to increase and reduce anti-apoptotic and pro-apoptotic protein levels, respectively, resulting in lesser cellular apoptotic rate when compared with placebo. The potential mechanism was thought mainly due to its anti-oxidant properties.

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