Glymphatic system dysfunction in alcohol use disorder: Current understanding and future directions

Table 1 Treatments targeting the glymphatic system

Treatment	Outcome	Mechanism	Ref.
High-intensity interval training	Alleviate cognitive dysfunction of STZ-induced AD rats, promote clearance of abnormal tau and Aβ	Shift astrocyte phenotype from A1 to A2, improve AQP4 polarization	[96]
Electroacupuncture therapy	Improve cognitive function of SMAP8 AD model mice, mitigate neuropathological damage in brain tissue	Suppress astrocyte reactivity, improve AQP4 polarity	[97]
VLIUS	Enhance influx of CSF tracer into perivascular spaces, promote clearance of brain interstitial solutes	TRPV4 in astrocytes activated by VLIUS, induce Ca2+ influx and CaM activation to promote AQP4 polarization	[98]
OAB-14	Improve cognitive impairment of 9-10-month-old APP/PS1 transgenic mice, promote Aβ clearance	Upregulate PPARγ-P2X7r-AQP4 pathway to increase AQP4 expression, promote AQP4 polarization by raising Agustin, SNTA-1 and ABCA1 Levels	[99]
L-3-n-butylphthalide	Enhance glymphatic clearance rate of APP/PS1 mice, reduce parenchymal Aβ deposition	Increase brain pulsatility, improve perivascular AQP4 Localization	[100]
Yuanzhi powder	Clear excessive Aβ deposits, improve cognitive defects and pathological damage of APP/PS1 mice	Improve AQP4 polarity distribution, upregulate transport function of MLV	[101]
Nano-plumber encapsulating pro-DHA and VEGF-C	reverse inflammatory microenvironment, enhance glymphatic system function	Reverse microglial inflammatory phenotype, restore phagocytic ability and protect vasculature, stimulate angiogenesis of meningeal lymphatics	[102]
GLP-1R agonists	Improve post-traumatic cognitive function in mice, increase fluid drainage in perivascular spaces	Suppress reactive gliosis, improve AQP4 polarization, reduce axonal injury and neuronal apoptosis	[103]
Cannabidiol	Improve motor, memory and cognitive functions, promote clearance of p-tau and Aβ	Improve AQP4 polarization, reduce inflammation, increase cerebral blood flow	[104]
Fingolimod	Reduce brain edema of DBI rats, mitigate axonal injury, restore glymphatic function	Improve AQP4 polarization, reduce inflammation, increase cerebral blood flow	[105]

Aβ: Amyloid-β; ABCA1: ATP-binding cassette subfamily A-1; AD: Alzheimer’s disease; APP/PS1: Amyloid precursor protein/presenilin 1; AQP4: Aquaporin 4; CaM: Calmodulin; CSF: Cerebrospinal fluid; DBI: Diazepam-binding inhibitor; DHA: Docosahexaenoic acid; GLP-1R: Glucagon-like peptide-1 receptor; MLV: Murine leukemia virus; P2X7r: P2X7 receptor; PPARγ: Peroxisome proliferator-activated receptor gamma; p-tau: Phosphorylated tau; SMAP8: Smooth muscle-associated protein 8; SNTA-1: Syntrophin alpha 1; STZ: Streptozotocin; TRPV4: Transient receptor potential vanilloid 4; VEGF-C: Vascular endothelial growth factor-C; VLIUS: Very low-intensity ultrasound.