Table 2.

Neuroprotective Role of GLP-1 Signaling Analogs in the Protection of Various Dementia Related Neurodegenerative Abnormalities

S. No	GLP-1 Signaling Activators	Brain Areas Affected	Neuro-Complications Prevented	Study Type	Dose and Route	Duration of Study	References
1.	Exendin-4 (GLP-1 agonist)	Cerebrum, Brain pericytes	↓Cerebral pathological neovascularization indices, ↑Learning and memory functions, ↓Diabetes-induced inflammation, ↓Oxidative stress, ↓Vascular-induced cognitive impairment and dementia	Pre-clinical study Control and diabetic mice, Human brain microvascular pericytes	Exendin-4: 30ng/kg per day	28 days	[226]
2.	Metformin (Direct, AMPK-dependent, GLP-1 activator)	CNS	↓Dementia risk in unmatched cohort (HR= 0.550; 95% CI), ↓Dementia risk in matched cohort (HR= 0.707; 95% CI)	Clinical study Retrospective, unmatched and matched-pair cohort study Mean age: 63 years, Morbidity: T2DM, no dementia at baseline	Prescribed doses	> 58.1 months	[225]
3.	Glitazone, Metformin (↑ GLP-1 in the plasma)	CNS	Glitazones ↓dementia risk (OR: 0.80), Metformin, prescribed as monotherapy (OR = 0.71) or as dual therapy with sulfonylureas (OR = 0.90), was associated with ↓dementia risk	Clinical study Retrospective, case-control study 8276 diabetes patients with dementia and 8276 diabetes patients without dementia, Mean age: 79.7 years, 56.2% women candidates	Prescribed doses	5 years	[223]
4.	Dipeptidyl-Peptidase 4 Inhibitors (↑ level of incretins like GLP-1)	CNS	↓Risk of dementia compared to sulphonyl urea use (HR= 0.66), ↓Risk of AD dementia (HR=0.64), ↓Risk of VD non-significantly (HR= 0.66)	Clinical study Population-based, retrospective observational cohort study, 7552 users of sulfonylureas and 7552 users of DPP-4 inhibitors, Age >60 years, with T2DM, dementia-free at baseline	Prescribed doses	1362 days	[216]
5.	Pioglitazone and Metformin	CNS	↓ Risk of dementia compared with those on metformin +sulfonylurea (HR 0.56; 95% CI 0.34, 0.93)	Clinical study Retrospective cohort study, 2,04,323 individuals with T2DM, receiving metformin-based dual therapy, Age: ≥18 years and ≥65 years, Dementia-free at baseline	At prescribed doses	3 months	[227]
6.	Pioglitazone (GLP-1activator)	CNS	↓ Dementia risk, Greater ↓ in dementia risk on prolonged use	Clinical study Retrospective cohort study 11,011 pioglitazone users, 11,011 never-users of pioglitazone Mean age: 59 years, No dementia at baseline	Prescribed doses	>20 months	[225]
7.	Exenatide (Long-acting, GLP-1 receptor agonist)	Caudate, Putamen	↑Neuronal survival pathways, ↑Mitochondrial function, ↓Neuro-inflammation	Clinical study Randomized, double-blind, placebo-controlled trial Age: 25–75 years	Exenatide- 2 mg, once weekly, subcutaneous injections	48 weeks exposure period, 2 weeks washout period	[228]
8.	Sitagliptin (DPP-4 inhibitor, ↓GLP-1 degradation and ↓glucagon secretion)	CNS	↑Glycemiccontrol, ↓Insulin requirement, ↑Cognitive function in elderly diabetic patients,	Clinical study Prospective, observational study 253 elderly patients with T2DM, with and without AD	Regular prescribed doses	6 months	[222]
9.	Pioglitazone (PPAR-γ agonist, activates GLP-1 receptor)	Substantia nigra, Striatum	↓Dementia incidence	Clinical study Prospective cohort study 1,45,928 subjects Age: ≥60 years	Prescribed doses, oral route	2 years	[229]
10.	Liraglutide (a novel GLP-1 analog)	Frontal cortex	↓ Insulin receptor aberrations, ↓Amyloid-β plaque load, ↓ IRS-1 pS616 levels, ↓Glial activation, ↓Astrocytosis	Pre-clinical study APPSWE/PS1dE9 mouse model of AD Age: 7 months	25 nmol/kg body weight, i.p., once daily	8 weeks	[230]
11.	Liraglutide (GLP-1 analog)	Hippocampus	↓Memory impairment, ↓Neuronal loss, ↑Synaptic plasticity, ↓Amyloid plaque deposition by 40–50%, ↓Inflammatory response, ↓Activated microglial cell numbers	Pre-clinical study AD transgenic mice APP/PS1 and WT littermate controls Age: 7-months-old	Systemic administration 25 nmol/kg body weight, i.p., once daily	8 weeks	[231]
12.	Liraglutide, Exenatide (GLP-1 receptor agonists)	Cerebral cortex, Hippocampus	↑ Axonal transport ↓Hippocampal IRS-1pSer, ↑Behavioral measures of cognition	Pre-clinical study Model: APP/PS1 Tg mice and WT controls Age: 13 to 14 months old	25 nmol/kg body weight, i.p. route	3 weeks	[232]
13.	GLP-1, Exendin-4 (a stable analog of GLP-1)	Hippocampus	↓Endogenous levels of amyloid peptide, ↓Dementia like-effect of amyloid β oligomers, ↓Neuronal death induced by amyloid β	Pre-clinical study In vitro: PC12 cell culture, In vivo: db+/db+mice	PC12 cells: GLP-1 (3.3, 33, and 330 ng/mL), exendin-4 (0.1, 1.0, and 10 µg/mL) Mice: GLP-1 (3.3 ng, 6.6 ng), exendin-4 (0.2 ng), via bilateral infusion	18 days	[233]
14.	Liraglutide (GLP-1 agonist)	Cerebral cortex	↑ Cerebral microvasculature, ↓Cerebral microaneurysms and leakage	Pre-clinical study Transgenic mice APP/PS1 and WT mice Age: 7-months old	Liraglutide - 25 nmol/kg body weight, saline (0.9% w/v), via i.p.injection, once daily	8 weeks	[219]
15.	Liraglutide (Novel GLP-1 analog, pre-treatment)	Hippocampal CA1 region	↓Aβ25–35-induced impairment of spatial learning and memory, ↑Late-phase long-term potentiation, ↑Intracellular cAMP level	Pre-clinical study Adult, male, Sprague Dawley rats Weight:230–250 grams	Liraglutide:2 µL, injected at a rate of 0.2 L/min, and 25 nmol/kg body weight by i.p. injection	2 weeks	[218]
16.	GLP-1	Hippocampus	↑Intracellular calcium levels, ↓ Calcium responses to glutamate, ↓Membrane depolarization, ↓Neuronal death induced by glutamate, ↑ Neuronal plasticity, ↑ Cell survival	Pre-clinical study In-vitro study Dissociated hippocampal cell cultures, Density: 80–100 cells/mm2	10 nM GLP-1 treatment	10 days	[234]
17.	GLP-1 receptor agonists	Substantia nigra, Striatum	↓Inflammatory response ↑ Insulin receptor signaling ↓Proinflammatory cytokine levels	Clinical study Meta-analysis of randomized controlled trials Adult participants, Body mass index: 25 or higher; with or without T2DM	Exenatide: twice daily and once weekly, Liraglutide: once daily at clinically relevant doses	20 weeks	[235]
18.	GLP-1 analog (Liraglutide)	Temporal lobe, Occipital lobe, Parietal lobe, Cerebellum	↑Glucose metabolism, ↓Decline of brain glucose consumption	Clinical study Randomized, placebo-controlled, double-blinded study, 38 AD patients	Liraglutide- 0.6 mg subcutaneously daily for 1 week, then 2 mg daily for 1 week, and then 1.8 mg daily	26 weeks	[221]
19.	Intra-nasal insulin detemir	Hippocampus, Amygdala, Pre-frontal cortex	↑Verbal memoryin APOE-€4 positive carriers, ↑Working memory in the 40 IU group, ↑Visuospatial working memory	Clinical study Total: 60 old subjects, 39 participants with amnestic MCI and 21 participants with probable AD with Mini-Mental State Examination scores >15	20 IU and 40IU, daily treatment for 3 weeks, via nasal drug delivery device	2 years	[220]
20.	Geniposide (a novel agonist for GLP-1)	Pheochromocytoma	↑Anti-apoptotic Bcl-2 protein level, ↑ Heme oxygenase-1, ↑Phosphorylation of c-Raf, MEK ↑Phosphorylation of MAPK, and p90RSK ↓Oxidative damage	Pre-clinical study In-vitro study Rat PC12 cell line, cultured in Dulbecco’s modified Eagle’s medium, at 37°Celsius with 5% CO2	GLP-1: 33 mg/l, Geniposide: 50 mg/l,	4 hours	[227,236]

Notes: Symbols: (↑) Increases, (↓) Decreases, (>) Greater than, (≥) Greater than or equal to, (<) Less than, (%) Percent.

Abbreviations: IU, International unit; OR, Odds ratio; HR, Hazard ratio; CI, Confidence interval; APP/PS1, Amyloid precursor protein/presenilin 1mutant form of Alzheimer’s disease; GLP-1, Glucagon like peptide-1; CA1, Cornu ammonis1; CNS, Central nervous system; cAMP, Cyclic AMP; i.p., Intra-peritoneal; AD, Alzheimer’s disease; VD, Vascular dementia; DPP-4, Dipeptidyl peptidase-4; IRS, Insulin receptor substrate; WT, Wild type; PC12, Pheochromocytoma cell 12; Bcl-2, B cell lymphoma-2; c-Raf, c-Rapidly accelerated fibrosarcoma; MEK, Mitogen-activated protein kinase kinase; MAPK, Mitogen-activated protein kinase; CO₂, Carbon dioxide; T2DM, Type 2 diabetes mellitus; APOE-€4, Apolipoprotein E, type epsilon 4 allele; MCI, Mild cognitive impairment; AMPK, AMP-activated protein kinase; PPAR-γ, Peroxisome proliferator-activated receptor gamma.