Table 2:

Potentially protective biological activity of pomegranate in neurodegenerative diseases.

Study type	Model	Treatment	Main findings	Reference
In vitro	The simplified human intestinal microbiota (SIHUMIx)	Pomegranate extract (0.5 or 5 mg/ml) for 24 h	Alters gut microbiota metabolism including increased production of GABA and SCFAs	Farag et al. (2020)
	Rat E-18 primary hippocampal neurons and SK-N-SH human neuroblastoma cells	Cotreatment with IPA (1–100 μM) and Aβ (1 μM) for 24 h	Protects against Aβ toxicity as seen by increased neuronal cell viability	Chyan et al. (1999)
	Rat PC12 neuronal cells	Cotreatment with IPA (1–100 μM) and Aβ (10 μM)	Inhibits Aβ-induced lipid peroxidation	Chyan et al. (1999)
Animal	Transient forebrain ischemia in Mongolian gerbils	Daily oral administration of IPA (10 mg/kg) for 15 days prior to ischemic insult	Increases neuron survival rate and decreases lipid peroxidation in the hippocampus	Hwang et al. (2009)
	APP/PS1 transgenic mouse model of AD	Daily oral administration of urolithin A (300 mg/kg) for 14 days	Improves spatial learning and memory	Gong et al. (2019)
			Enhances hippocampal neurogenesis
			Decreases amyloid plaque deposition, reduces reactive glial cells, and lowers concentrations of TNF-α and IL-1β in cortex and hippocampus
			Increases p-AMPK and decreases p-p65NFкB, p-p38MAPK, BACE1, and APP in cortex and hippocampus
	Rotenone-induced rat model of PD	Daily oral administration of sixfold concentrated pomegranate juice (500 mg/kg) for 10 days prior to rotenone injection followed by 35 days treatment with pomegranate juice and rotenone	Reduces neurodegeneration in substantia nigra	Kujawska et al. (2020)
			Decreases ratio of α-synuclein oligomers to monomers demonstrating diminished aggregation of α-synuclein
			Reduces lipid peroxidation as indicated by lowered MDA levels
			Upregulates antioxidant systems as measured by increased levels of catalase, GSH, GSH-Px, and GSH-S-transferase
			Increases expression of mitochondrial aldehyde dehydrogenase 2 indicating improved protection against oxidative stress
	6-OHDA mouse model of PD	Daily intraperitoneal injection of urolithin A (10 mg/kg) for 7 days prior to 6-OHDA	Increases survival of dopaminergic neurons in the nigrostriatal system	Liu et al. (2022)
			Improves motor function measured by the pole, suspension, rotarod, and apomorphine-induced rotation tests
Human clinical trials	Healthy middle-aged and older adults	Daily consumption of 240 ml (8 ounces) pomegranate juice for 12 months	Preserves visual memory function over a 12-month period as measured by significantly better BVMT-R learning scores compared to the placebo group	Siddarth et al. (2020)
	Nondemented older adults with self-reported memory complaints	Daily consumption of 240 ml (8 ounces) pomegranate juice for 28 days	Improves verbal and visual memory functions as demonstrated by cognitive testing and fMRI	Bookheimer et al. (2013)
			Increases brain activity in the basal ganglia, thalamus, left inferior frontal gyrus, left middle frontal gyrus, left inferior temporal gyrus, left and right occipital lobes, left and right fusiform gyrus, and the parahippocampal regions
	Ischemic stroke patients	Consumption of 1 g pomegranate polyphenol pill (equivalent to 240 ml juice) twice daily, starting 2 weeks after stroke	Improves neuropsychological functions as measured by increased RBANS score, especially in visuospatial/constructional and language domains	Bellone et al. (2019)

6-OHDA, 6-hydroxydopamine; AD, Alzheimer’s disease; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; Aβ, amyloid β; BACE1, β-site APP cleaving enzyme 1; BVMT-R, Brief Visuospatial Memory Test-Revised; fMRI, functional magnetic resonance imaging; GABA, gamma-aminobutyric acid; GSH, glutathione; IL, interleukin; IPA, indole-3-propionic acid; MAPK, mitogen-activated protein kinase; MDA, malondialdehyde; NF, nuclear factor; p, phosphorylated; PD, Parkinson’s disease; PS1, presenilin 1; Px, peroxidase; RBANS, Repeatable Battery for Assessment of Neuropsychological Status; SCFA, short-chain fatty acid; and TNF-α, tumor necrosis factor α.