Table 1.

Summaries of studies reporting HMGB1 targeted therapies in AD and related pathology.

S.N.	Interventions	Model	Treatment Schedule	Observations	References
1	HMGB1 short hairpin RNA (shRNA)	Aβ25–35-induced (25 μmol/L) neuroinflammation in hippocampal neuron cultures	Pre-treated for 24 h	HMGB1 shRNA inhibits nuclei to cytoplasmic translocation of HMGB1 after treatment with Aβ25–35. HMGB1 shRNA inhibits NF-ĸB activity, reduced RAGE and TLR4 expression and inhibited inflammatory cytokine (HMGB1, IL-1β, IL-6, and TNF-α) secretion after Aβ25–35 treatment.	[18]
2	Anti-HMGB1 mAb (1 mg/kg, S.C. injection) (1 injection/week)	5xFAD transgenic mice overexpressing the mutant human APP	Administered for 1–6 months or 3–6 months	Anti-HMGB1 mAb treatment decreases the amount of Aβ aggregates and the oligomers as well as enhance Aβ phagocytosis by microglia. Treatment with Anti-HMGB1 mAb inhibited the degeneration of neurite even in the presence of Aβ plaques and completely ameliorated the cognitive dysfunction.	[37]
3	Glycyrrhizic acid (GA) (50 and 100 mg/kg, I.P.)	LPS (250 μg/kg) -induced neuroinflammation and cognitive impairment in the C57 mice (4–5 weeks old)	Once daily for 1 week	GA treatment ameliorate LPS-induced cognitive decline and neuronal damage by decreasing the escaped latency in MWM test and upregulating the number of Nissl-stained cells and normal neurons in the hippocampus respectively. Treatment with GA reduces LPS-induced neuroinflammatory response in cortex and hippocampus (TNF-α and IL-1β).	[109]
4	Glycyrrhizin (GL) (16.8 mg/kg, I.P.)	p35-/-/Tg2576 mice (p35 deletion in Tg2576 mice)	Every alternate day for 1 week	GL treatment reduced neuronal cell death	[42]
5	GL (30 mg/kg, orally)	Surgery induced cognitive decline in C57BL/6 mice	Once daily for 3 days pre-operatively	GL pre-treatment reduces splenectomy surgery-induced neuroinflammation (TNF-α, IL-6 and IL-1β). Pre-treatment with GL attenuates the increases of Hippocampal Aβ levels, Tau phosphorylation and HMGB1 upregulation induced splenectomy surgery. GL rescued the splenectomy surgery induced spatial memory deficits as demonstrated by the shorter swimming latency as well as distance in MWM test.	[110]
6	GL (30 and 50 mg/kg, orally)	LPS (3 mg/kg, I.P.)-induced neuroinflammation and cognitive impairment in the C57BL/6 mice	Once a day for 3 days prior to LPS injection	GL ameliorated the LPS-induced memory deficit as evident by prolonged swimming time in MWM trial. GL administration reduced the markers of inflammation (TNF-α and IL-1β mRNA) and protein expression of COX-2 and iNOS.	[108]
7	18α-glycyrrhetinic acid (GA) (20  μg/mL)	AD nematode models (WT Caenorhabditis elegans)	-	Administration of 18α-GA increased the levels of proteasome activities leading to a skinhead-1 and proteasome activation-dependent life span extension. 18α-GA treatment reduces Aβ toxicity and reduces Aβ-induced neuronal cell death.	[132]

HMGB1, High mobility group box 1; GL, Glycyrrhizin; GA, Glycyrrhizic acid; AD, Alzheimer’s disease AD; RAGE, Receptor for advanced glycation end products; TLR4, Toll-like receptor 4; Aβ, Amyloid beta; APP, Amyloid precursor protein; WT, Wild-type; FAD, Familial AD; IL, Interleukin; IBA1, ionized calcium-binding adapter molecule 1; iNOS, Inducible nitric oxide synthase; COX-2, Cyclooxygenase-2; NF-κB, Nuclear factor κ light chain enhancer of activated B cells; TNF-α, Tumor necrosis factor-α, LPS, Lipopolysaccharide; MWM, Morris water maze; SC, Subcutaneous.