Table 1.

Summary on the influence of inflammatory conditions and diseases on the expression and functionality of the BBB drug transporters.

Transporter	BBB Expression	Function	Disease Impacted and Key Findings	References
ATP-binding cassette (ABC) transporters
ABCB1 (P-gp)	Luminal (apical)	Efflux	Neuroinflammation: ABCB1 expression and/or function dysregulation were described in states of chronic neuroinflammation. AD: ABCB1 plays a role in the clearance of Aβ peptides from the brain across the BBB. ABCB1 decreased expression, and dysregulation might contribute to the progression of Aβ deposition in the brain. Epilepsy: ABCB1 overexpression and increased activity suggested possible explanation for the lack of drug response and reduced brain accumulation of anti-epileptic drugs. Stroke: ABCB1 expression and activity were mostly upregulated in ischemia and stroke. ABCB1 inhibitors were proposed to improve therapeutic effects of neuroprotective drugs in ischemic brain. ALS: ABCB1 overexpression and increased function were extensively reported and highlighted the role of ABCB1 in mediating pharmacoresistance in ALS. MS: ABCB1 cerebrovascular expression was reduced and function was impaired. ABCB1 expression was increased in reactive astrocytes in human brain of MS patients.	[122,185,188,199,200,203,204,205,206,207,208,209,210,211,212,213,214,215,216]
ABCG2 (BCRP)	Luminal (apical)	Efflux	Neuroinflammation: ABCG2 expression and/or function dysregulation were reported in chronic neuroinflammatory conditions. AD: ABCG2 expression and function were upregulated in AD. ABCG2 was shown to participate in the clearance of Aβ peptides and transport across the BBB and, possibly, acting as a gatekeeper at the BBB (by interacting and preventing the entry of blood Aβ peptides in the brain). Epilepsy: ABCG2 expression and activity were upregulated in epilepsy. ABCG2 could decrease brain accumulation of anti-epileptic drugs. Stroke: ABCG2 expression and activity were mostly increased in ischemia and stroke. ALS: ABCG2 expression and function were mainly upregulated in ALS and played a role in pharmacoresistance in ALS.	[128,199,211,216,217,218,219]
ABCC1 (MRP1)	Luminal (apical) and basolateral	Efflux	AD: ABCC1 has an important role in cerebral Aβ protein clearance across the BBB. Decreased expression and dysregulation might contribute to the progression of Aβ deposition and accumulation in the brain. Epilepsy: ABCC1 overexpression and increased activity induced by status epilepticus were associated with reduced anti-epileptic drugs levels in the brain and reduced efficacy. Stroke: ABCC1 dysregulation in response to ischemia was reported. Studies indicated a reduced expression of ABCC1 in ischemic brain capillaries. MS: ABCC1 expression was increased in reactive astrocytes in the brain of MS patients.	[127,199,220,221,222,223]
ABCC2 (MRP2)	Luminal (apical)	Efflux	Neuroinflammation: Abcc2 transport activity and protein expression were increased in rat or mouse brain capillaries in response to activation of Nrf2. Epilepsy: ABCC2 overexpression and increased activity induced by status epilepticus was associated with reduced anti-epileptic drugs levels in the brain and reduced efficacy.	[137,199,222]
ABCC4 (MRP4)	Luminal (apical) and basolateral	Efflux	AD: ABCC4 increased protein expression was detected at in the hippocampal sections from AD brain.	[207,222]
ABCC5 (MRP5)	Luminal (apical)	Efflux	Stroke: Abcc5 expression in rat brains was upregulated following ischemic events induced by middle cerebral artery occlusion.	[137,216]
ABCA7	Not clear	Efflux	AD: GWAS studies identified risk variants in ABCA7 with direct functional impact suggesting evidence of its role in AD risk. Its role could be linked to the regulation of cholesterol homeostasis and Aβ efflux at the BBB. Significant increase of insoluble Aβ and plaque load in the brains of Abca7-deficient mice. The underlying mechanism of ABCA7 role in AD pathogenesis is still unclear.	[132,224,225,226,227,228]
Organic Anion Transporting Polypeptides
SLCO1A2 (OATP1A2)	Luminal (apical)	Uptake	Stroke: The rodent ortholog of human SLCO1A2, Slco1a4, expression was increased following cerebral hypoxia and subsequent reoxygenation stress, a central component of ischemic stroke.	[31,66,70]
SLCO2B1 (OATP2B1)	Luminal (apical)	Uptake	Aging: SLCO2B1 expression was decreased in the gray matter BBB of both AD and age-matched controls in different brain regions.	[120]
Others
SLC27A1 (FATP1)	Basolateral	Efflux	AD: SLC27A1 expression was shown to be reduced and impaired after exposure to Aβ peptides in human brain endothelial cells. SLC27A1 was shown to impair the transport of docosahexaenoic acid into the brain.	[229,230]
SLC29A1 (ENT1)	Not clear	Efflux/uptake?	Aging: SLC29A1 expression was decreased in the gray matter BBB of both AD and age-matched controls in different brain regions.	[120]
SLC2A1 (GLUT1)	Luminal (apical) and basolateral	Uptake	Epilepsy: SLC2A1 was downregulated in regions within and surrounding the seizure focus.	[141]

Abbreviation: Aβ, amyloid beta; AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; BBB, blood–brain barrier; BCRP, breast cancer resistance protein; ENT1, equilibrative nucleoside transporter 1; FATP1, fatty acid transport protein 1; GLUT1, glucose transporter 1; GWAS, genome-wide association studies; MRP, multidrug resistance-associated protein; MS, multiple sclerosis; Nrf2: nuclear factor erythroid-derived 2-like factor; OATP, organic anion transporting polypeptides.