Table 3.

Therapeutics targeting signalling pathways common in both T2DM and PD

Therapeutic drug	Mechanism	Model	Dosage	Methods	Result	Conclusion	References
Metformin	Amyloid aggregation	Healthy human blood	200 mmol/L	• Spectrophotometry • In vitro assays	• ↑anti-AChE • ↑anti-Aβ aggregation	Metformin may be regarded as an effective adjuvant to donepezil	[233]
	Oxidative stress and mitochondrial dysfunction	ASCs	25 µmol/L	• Western blot • Immunoblot • SDS-PAGE	• ↓oxidative stress • ↓mitochondrial dysfunction • ↑adipogenicity • ↑insulin sensitivity	Metformin may improve impaired adipogenesis and insulin sensitivity	[234]
	Microglial activation and chronic inflammation	BV-2 and bEnd3 cells	50 mg/kg	• Western blot • Immunohistochemistry • PCR	• ↓p38 MAPK phosphorylation • ↓pro-inflammatory cytokines • ↓TLR-4 mRNA expression • ↓IL-6 • ↓TNF-α mRNA expression	Metformin suppresses microglial activation by increasing AMPK phosphorylation	[235]
GLP1R agonists/GIP receptor	Amyloid aggregation	Clonal mouse insulin-secreting cell line (min6)	25 mM	• RT-PCR • ELISA • Western blotting	• ↓hIAPP-induced LC3II/I ratio • ↓hIAPP-induced cleaved caspase-3 • ↓p62 expression	Exendin-4’s has the potential in the treatment of diabetic ß-cell failure	[236]
	Microglial activation and chronic inflammation	Mice	5.0 mg/ml	• Immunofluorescence • Western blotting • Immunofluorescence staining	• ↓Iba-1 • ↓IL-1β • ↓TNF-α release • ↓TNC microglial number • ↑allodynia • ↓CGRP and c-fos in the TNC	GLP-1R agonist liraglutide might represent a new therapeutic approach for treating chronic migraine	[237]
	Impaired synaptic plasticity	Mice	_	• Open field assessment • Object recognition task • Water maze task	Glp1r−/− mice • ↓motor activity • Normal exploratory activity and anxiety levels	GLP-1R is crucial for some forms of memory formation and synaptic plasticity	[238, p. 20]
	Microglial activation and chronic inflammation	Mice	25 nmol/kg	Rotarod and grip strength assessment	• ↓increased levels of activated microglia and astrocytes ••••↑ GDNF	GLP-1/GIP dual agonist has the potential to exhibit superior neuroprotective effects	[239]
	Impaired synaptic plasticity	Mice	10 nmol/kg	• Western blotting • Water maze • Probe test	• ↓memory loss • ↑synaptic plasticity • ↓amyloid plaques • ↓pro-inflammatory cytokine levels	GLP-1/GIP dual receptor agonist was more effective at reversing memory loss	[240]
Insulin	Oxidative stress	Cultured cortical neurons	10 M	• MTT assay • SDS-PAGE • UV-spectrophotometry	• ↓oxidative stress • ↓necrotic and apoptotic cell death • ↓ascorbate/Fe2 + -mediated lipid and protein oxidation	Insulin may help reduce the damage caused by oxidative stress that develops in several neurodegenerative diseases	[31]
	Impaired synaptic plasticity	Mice	20 µl	• Immunohistochemistry and image analysis • Western blotting	• ↓rapamycin complex 1 (mTORC1)	Intranasal insulin prevents general anaesthesia-induced apoptosis of hippocampal cells and deficits in synaptic plasticity and memory	[241]
	Microglial activation and chronic inflammation	Microglial cell line	125 ng/ml	• Western blot • Immunocytochemistry • Phagocytosis assay	• ↑ phagocytic activity • ↓NO • ↓TNF production • ↓ROS	Insulin has beneficial effects on CNS injury or neurodegenerative conditions	[242]

PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; GSK-3 beta, glycogen synthase kinase-3 beta; FOXO1, Forkhead box protein O1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; mTOR, mammalian target of rapamycin; DA4-JC, dual GLP-1/GIP receptor agonist; ASCs, adipose-derived stromal cells; HIAPP, human islet amyloid polypeptide; TNC, trigeminal nucleus caudalis; CM, chronic migraine; AMPK, 5' AMP-activated protein kinase; NO, nitric oxide; TNF, tumour necrosis factor; ROS, reactive oxygen species; iNOS, inducible NO synthase; AChE, human acetylcholinesterase; Aβ, amyloid beta; bEnd3, endothelial cells; TLR-4, Toll-like receptor-4; TNF-α, tumour necrosis factor-α; GDNF, glial derived neurotrophic factor