Table 1:

Potentially protective biological activity of grape products in neurodegenerative diseases.

Study type	Model	Treatment	Main findings	Reference
In vitro	Rotenone-treated human SH-SY5Y-derived neurons	Rotenone (100 μM) for 24 h, followed by liposomes containing a grape seed and skin extract (400 μg/ml) for 48 h	Treatment with liposomes rescues neuronal cell viability	Marino et al. (2021)
			Reduces intracellular ROS production
	6-OHDA-treated primary murine midbrain dopaminergic neurons	Grape seed and skin extract (500 or 1000 μg/ml) for 6 h prior to 6-OHDA insult	Reduces apoptosis through inhibition of the caspase-3 pathway, downregulation of the proinflammatory NFκB signaling pathway, and lowering of ROS production by dopaminergic neurons	Ben Youssef et al. (2021)
	LPS-treated Caco-2 cell model of intestinal epithelial barrier	Resveratrol-3-O-sulfate (100 μM)	Improves intestinal barrier integrity as measured by upregulated mRNA expression of occludin, ZO-1, claudin-1, and claudin-4	Zhang et al. (2021)
	PD patient-derived fibroblasts	Resveratrol (25 μM) for 24 or 48 h	Rescues mitochondrial function through AMPK/SIRT1/PGC-1α pathway	Ferretta et al. (2014)
			Increases gene expression of TFAM and cytochrome c leading to improved mitochondrial oxidative phosphorylation capacity and reduced ROS production
	MPP+ treated rat PC12 neuronal cell model of PD	Pretreatment with resveratrol (0.1 μM) 3 h prior to MPP+	Increases survival rate of neurons	Bournival et al. (2009)
			Normalizes Bax to Bcl-2 protein ratio
			Inhibits cytosol to nucleus translocation of AIF and reduces release of apoptosis-inducing cytochrome c from mitochondria
	Rotenone-treated murine BV-2 microglia	Pretreatment with resveratrol (50 μM) 1 h prior to rotenone	Inhibits rotenone-induced production of ROS, MDA, IL-6, IL-1β, and TNF-α	Sun et al. (2021)
Animal	Mouse model of stress by immobilization	Oral pretreatment for 5 days with 200 μl polyphenol-enriched grape juice prior to stress	Reduces mRNA levels of proinflammatory mediators IL-6 and TNF-α to those observed in unstressed animals	Bobadilla et al. (2021)
			Normalizes indicators of oxidative stress (NOX2 and HMOX-1)
	Scopolamine mouse model of AD	Pretreatment and cotreatment with grape seed oil (2 mg/kg) daily for 10 days	Improves spatial memory, as tested by Morris water maze	Berahmand et al. (2020)
			Increases brain levels of acetylcholine
	6-OHDA mouse model of PD	Grape seed and skin extract administered intraperitoneally prior to 6-OHDA insult	Improves survival of dopaminergic neurons in SNpc	Ben Youssef et al. (2021)
			Enhances motor function as demonstrated by open-field test
	Senescence-accelerated mouse model of aging	Daily oral administration of resveratrol (25–100 mg/kg) for 8 weeks	Restores cognitive functions to levels seen in aging-resistant mice	Liu et al. (2012)
			Increases antioxidant activity as measured by upregulated SOD mRNA and enzymatic activity, increased GSH-Px activity, and decreased MDA
			Protects from oxidative stress-induced mitochondrial DNA damage as indicated by lower percentage of mtDNA deletions
	APP/PS1 mouse model of AD	Diet supplemented with 0.35% resveratrol for 15 weeks prior to the onset of amyloidosis	Smaller Aβ plaques	Capiralla et al. (2012)
			Less reactive microglia
Human clinical trials	Elderly persons with mild cognitive impairment	Consumption of 36 g grape powder in 240 ml (8 ounces) water twice per day for 6 months	Preserves metabolic activity in the left superior posterolateral temporal cortex and right posterior cingulate cortex	Lee et al. (2017)
	Patients with mild to moderate AD	Daily consumption of resveratrol (0.5–2 g) for 52 weeks	Stabilizes the decline in plasma and CSF Aβ40 levels	Turner et al. (2015)
	Patients with mild to moderate AD	Daily consumption of resveratrol (0.5–2 g) for 52 weeks	Stabilizes the decline in CSF Aβ40 and Aβ42 levels	Moussa et al. (2017)

6-OHDA, 6-hydroxydopamine; AD, Alzheimer’s disease; AIF, apoptosis-inducing factor; AMPK/SIRT1, AMP-activated protein kinase/sirtuin-1; APP, amyloid precursor protein; Aβ, amyloid beta; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; CSF, cerebrospinal fluid; GSH, glutathione; HMOX-1, heme oxygenase 1; IL, interleukin; LPS, lipopolysaccharide; MDA, malondialdehyde; MPP+, 1-methyl-4-phenylpyridinium ion; mtDNA, mitochondrial DNA; NF, nuclear factor; NOX2, NADPH oxidase 2; PD, Parkinson’s disease; PGC, peroxisome-proliferator-activated receptor gamma coactivator; PS1, presenilin 1; ROS, reactive oxygen species; Px, peroxidase; SNpc, substantia nigra pars compacta; SOD, superoxide dismutase; TFAM, mitochondrial transcription factor A; and TNF-α, tumor necrosis factor α.