TABLE 1.

Summary of some natural products with AD and PD therapeutic potential.

Natural products	Diseases	In-vitro/vivo models/human trial	Dose and period of treatment	Treatment time	Mechanism	Activation or inhibition of PI3K/AKT pathway	References
Curcumin	AD	N2a/WT cells	5 μM for cell line and 1or 0.16 g/kg for animals	6 months	Decrease in Caveolin-1, inactivation of GSK-3 and inhibition of abnormal excessive tau phosphorylation, bax and increase in Bcl-2	Activation	Sun et al. (2017)
	PD	APP/PS1 transgenic mice
Dihydromyricetin	AD	D-gal-induced aging rat model	The doses of 100 and 200 mg/kg	5 weeks	Decrease the expression of caspase-3, p53 and p62, up-regulate Bcl-2 and SIRT1 activity, suppress aging-related astrocyte activation and inhibiting mTOR signal pathway as well as down-regulate miR-34a	Activation	Kou et al. (2016)
	PD	Sprague-dawley rats
Salidroside	AD	Transgenic drosophila AD models	Concentration of 50,100,200 μM	24 h	Decrease aβ levels and aβ deposition, increase AKT phosphorylation level p-mTOR or p-p70S6K level	Activation	Zhang et al., (2016a)
		C57BL mice	Concentration of 0.3 mg/ml	2–12 months	Reduce the aggregation of aβ and improve synaptic structure. Activation of PI3K/AKT/mTOR signaling pathway		Wang et al. (2020)
		APP/PS1 transgenic mice
Arctigenin	AD	ICR mice	The doses of 10, 40, or 150 mg/kg for animals	16 days	Inhibit the production of phosphorylated tau, and inhibition of the PI3K/akt/gsk-3β signaling pathway	Activation	Qi et al. (2017)
Schizandrol A	AD	SH-SY5Y cells or primary hippocampal neurons	Concentration of 2 μg/ml	24 h	Suppress the ratio of Bax/Bcl-2 and caspase-3, increase of p62, and decrease of LC3-II/LC3-I, Beclin-1, decreased ratios of p-Tau/Tau	Activation	Song et al. (2020)
Ginsenoside Rg2	AD	Male sprague-dawley rats	The doses of 25,50,100 mg/kg/day	6 days	Increase the Bcl-2/Bax ratio, attenuate the cleavage of caspase-3, and enhance the phosphorylation of AKT.	Activation	Cui et al., (2020)
Notoginsenoside R1	AD	C57BL/6J mice and APP/PS1 mice	Dose of 5 mg/kg/day	6 months	Improve cell viability, reduce the cleavage of Navb2 by BACE1 suppression, and also correct the abnormal distribution of Nav1.1a	Activation	Hu et al. (2020)
Fructus broussonetiae	AD	APP/PS1 double-transgenic mice	0.1, 0.15,0.3 g/ml for mice, and 150 mg/kg for rabbits	2 months	Increase p-AKT and ß-catenin signaling, decrease caspase-3,caspase-9, and levels of aβ and phosphorylate tau proteins	Activation	Li Y.-h. et al. (2020)
		Rabbits		10 days
Icariin	AD	SAMP8 mice model of AD	The doses of 60 mg/kg	22 days	Down-regulate the expression of BACE1 to reduce the expression of cytotoxic Aβ 1-42, and increase the Bcl-2/Bax ratio	Activation	Wu et al. (2020)
	PD	Ovariectomized PD mice, doparminergic MES23.5 cells	The doses of 50/100/200 mg/kg	13 days	Increase the DA content, the Bcl-2 and attenuate the increase of bax and caspase-3 protein levels, active PI3K/AKT or MEK/ERK signaling pathway		Chen et al. (2017)
Baicalein	AD	PC12 cells	Concentration of 40/60/80 μM	2 days	Increase the cell viability and niacin level. Inhibit Aβ 25–35-induce cytotoxicity by restraining the levels of ROS, and increasing the level of MMP and mitochondrial respiratory complex I	Activation	Gao et al. (2020)
	PD	Sprague-dawley rats	The doses of 30 mg/kg/day	7 days	Reduce procaspase-1, caspase-3 and elevate active caspase-1 levels		Zhao et al. (2017)
				9 days
Baicalin	PD	Sprague-dawley rats	The doses of 25 mg/kg	4 weeks	Increase the expression of mTOR, p-mTOR, AKT, p-AKT, GSK-3β, and p-GSK-3β	Activation	Zhai et al. (2019)
Apigenin	PD	SH-SY5Y cells, C57BL/6 mice	10,20,40,100 μM for cells and 50 mg/kg/day for mice	2h and 15 days	Upregulate the p-PI3K/PI3K ratio and p-AKT/AKT ratio while downregulate Bax/Bcl-2 ratio and caspase-3 activity, improve the lesioned neurobehavior	Activation	Hu et al. (2018)
Amentoflavone	PD	C57BL/6 mice	The doses of 50 mg/kg/day	15 days	Elevate the viability and alleviate apoptosis, restore the decreased TH expression, inhibite the activation of caspase-3 and p21 but increase the Bcl-2/Bax ratio, activate PI3K/AKT and ERK signaling pathways	Activation	Cao et al. (2017)
Puerarin	PD	SH-SY5Y cells, sprague–Dawley rats	10,50,100,150,200 µM for cells and 50 mg/kg for animal	12 h, 7 days	Elevate the viability, mitigate intracellular oxidative stress and ROS, up-regulate TH and VMAT2 expressions, and dopamine levels, alleviate behavioral defects of PD.	Activation	Zhang et al. (2014)
Tovophyllin A	PD	Primary cortical neurons, C57BL/6 mice	The doses of 40 mg/kg	24 h	Alleviate MPTP-induced behavioral dysfunctions and DA neuron loss, increase the phosphorylation of AKT and GSK-3β	Activation	Huang et al. (2020)
Berberine	PD	SH-SY5Y neuroblastoma cells	Concentration of 10–5,10–4,10–3, 10–2,10–1,1,10, and 100 µM	24 h	Up-regulate the Bcl-2, downregulate the bax and caspase-3, activate PI3K/AKT signaling pathway	Activation	Deng et al. (2020)
Schisantherin	AD	Differentiated rat pheochromocytoma PC12 cells	SCH (50 μM) and NKT (10 μM)	24 h	Activate the PI3K/AKT/GSK-3β/mTOR pathway, and inflammatory related proteins such as NF-κB, IKK, IL-1β, IL-6 and TNF-α are decreased	Activation	Qi et al. (2020)
Schisandrol A	PD	C57BL/6J mice	The doses of 10,20,30 mg/kg	2 weeks	Decrease the focal encephalomalacia and inhibite the striatal degeneration, enhance the PI3K/AKT pathway, inhibit the IKK/IκBα/NF-κB pathway, reduce neuronal inflammation and oxidative stress, and enhance the survival of DA neurons in the brain of mice	Activation	Yan et al. (2019)
Paeoniflorin	PD	C57BL/6 mice	The doses of 7.5,15,30 mg/kg	1 week	Prevent the TH and DAT protein decrease induced by MPTP, prevent the striatal p-AKT (Ser473) protein decrease, attenuate caspase-3 and caspase-9 activation	Activation	Zhao et al. (2017)
Cannabidiol	PD	The human neuroblastoma cell line SH-SY5Y	Concentration of 10 μM	24 or 48 h	Decrease LC3-II levels, activate the ERK and AKT/mTOR pathways and modulate autophagy	Activation	Gugliandolo et al. (2020)
Lycium barbarum polysaccharide	PD	C57BL/6 mice	The doses of 100 or 200 mg/kg	21 days	Up-regulate the TH level, inhibit the oxidative stress in the midbrain, and inhibit the aggregation of a-synuclein, downregulated LC3-II and beclin expression, activate the AKT/mTOR pathway through inhibiting PTEN.	Activation	Wang et al. (2018b)
Astragalus polysaccharides	PD	PC12 cell	Concentration of 50,100,200 μM	24 h	Promote the phosphorylation of AKT and mTOR, and up-regulate the expression of PTEN.	Activation	Tan et al. (2020)
Crocin	PD	Adult male wistar rats	The doses of 30 mg/ml/day	1 month	Increase active form of AKT, reduce expression and activity of FoxO3 and GSK-3β, elevate miRNA-221 expression, decrease pro-apoptotic caspase-9 and enhance anti-apoptotic Bcl-2	Activation	Salama et al. (2020)
Asiatic acid	PD	C57BL/6 mice	The doses of 25,50,100 mg/kg		Increase the phosphorylation of PI3K, AKT, GSK-3β and mTOR, inhibition of JNK, ERK and P38 MAPK-mediated signaling pathways	Activation	Nataraj et al. (2017)

Aβ, amyloid-β; AKT, protein kinase B; BACE1, amyloid precursor protein cleaving enzyme one; Bad, Bcl-xL/Bcl-2-associated death promoter homologue; caspase-3, cysteine protease protein; ERK, extracellular signal-regulated kinase; GSK-3β, glycogen synthase kinase-3β; HO-1, heme oxygenase-1; IKK, IκB kinase; IL-1β, interleukin-1β; IL-6, interleukin-6; JNK, c-Jun NH(2)-terminal kinase; LC3-II/LC3-I, the autophagosome-associated protein; MAPK, mitogen-activated protein kinases; MMP, mitochondrial membrane potential; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa B; p53, tumor suppressor gene; p62, the atypical protein kinase C-interacting protein; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; SD, Sprague-Dawley; SIRT1, Silent mating type information regulation two homolog-1; TNF-α, tumor necrosis factor-alpha.