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The canine blood-brain barrier in health and disease: focus on brain protection

bynewsdesk
January 17, 2025

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Review


doi: 10.1080/01652176.2025.2450041.


Epub 2025 Jan 10.

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Review

Dimitri Bassalo et al.


Vet Q.


2025 Dec.

Abstract

This review examines the role of the canine blood-brain barrier (BBB) in health and disease, focusing on the impact of the multidrug resistance (MDR) transporter P-glycoprotein (P-gp) encoded by the ABCB1/MDR1 gene. The BBB is critical in maintaining central nervous system homeostasis and brain protection against xenobiotics and environmental drugs that may be circulating in the blood stream. We revise key anatomical, histological and functional aspects of the canine BBB and examine the role of the ABCB1/MDR1 gene mutation in specific dog breeds that exhibit reduced P-gp activity and disrupted drug brain pharmacokinetics. The review also covers factors that may disrupt the canine BBB, including the actions of aging, canine cognitive dysfunction, epilepsy, inflammation, infection, traumatic brain injury, among others. We highlight the critical importance of this barrier in maintaining central nervous system homeostasis and protecting against xenobiotics and conclude that a number of neurological-related diseases may increase vulnerability of the BBB in the canine species and discuss its profound impacts on canine health.


Keywords:

P-glycoprotein (P-gp/ABCB1/MDR1); aging; brain endothelial cells (BECs); epilepsy; infection; traumatic brain injury (TBI).

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures


Figure 1.



Figure 1.

The canine neurovascular unit (NVU) and the BBB. The canine NVU is comprised of an intricate network of various Central nervous system (CNS) cells, including astrocytes and their foot processes (AFP), brain endothelial cells (BECs), pericytes, and extracellular matrix components (basement membrane) that regulate brain blood flow and are responsible for sustaining a functional BBB. Tight-junction proteins bind BECs and prevent paracellular transfer. P-gp (MDR1/ABCB1) represents a critical ABC transporter located on the apical surface of the BEC. Together, tight junctions and P-gp prevent the entry of several systemic blood-borne pharmacological and physiological substrates from entering the brain parenchyma. Publication license: BioRender PO27AHSJ8X.


Figure 2.



Figure 2.

The brain microvascular system. Brain-blood supply in canine species branches from the cerebral arterial circle (the circle of Willis) and the caudal cerebellar arteries of the vertebrobasilar system. These main arteries branch into perforating arteries of the brain, gradually transitioning from macro- to micro-brain vasculature enriched with astrocytes foot processes (AFP), perycites, brain endothelial cells (BECs), and extracellular matrix components (basement membrane). Factors that regulate BBB function comprise intercellular signaling among AFPs, pericytes and BECs, as well as blood pressure and frictional forces (wall shear stress) imposed by the cardiact output and the local blood flow regulation in the brain. Publication license: BioRender AW27AQEUIE.


Figure 3.



Figure 3.

ABCB1 (MDR1) in the BBB of the canine species. (a) Examples of transporter systems in brain endothelial cells (BECs) and their respective solutes transported via these mechanisms: lipophilic diffusion (alcohol, nicotine and benzodiazepine), paracellular transport (small hydrophilic solutes), receptor-mediated endocytosis/transcytosis (iron often bound to transferrin and insulin), transporter-mediated transport (glucose, amino acids, nucleosides and small intermediate metabolite), efflux transport – exemplified by the P-gp transporter, encoded by the ABCB1 gene (nutrients, xenobiotics and environmental toxins). (b) Heterozygote or homozygote mutation of the ABCB1 gene in dogs may lead to partial or full loss of P-gp function in BECs resulting in increased brain exposure to xenobiotics and environmental toxins in dogs carrying these mutations. Publication license: BioRender MR27AQFI08.


Figure 4.



Figure 4.

Heatmap of breed frequency of ABCB1 (MDR1) gene mutation and new breeds recently shown to carry the ABCB1 gene mutation. Collie, longhaired whippet and Australian Shepherds are breeds with the highest ABCB1 gene mutation frequency, whereas Border Collies, boxers and siberian huskies exhibit the lowest frequencies. New breeds carrying a higher frequencing of mutation include barbado da terceira and black mouth cur. Publication license: BioRender QX27AHS4N3.


Figure 5.



Figure 5.

Examples of microorganism interactions in the canine BBB and possible effects on P-gp function. SARS-CoV-2 may potentially decrease BBB tight junction (claudin 5), laminin and collagen IV levels and reduce pericyte coverage, as well as be associated with small vessel disease and neurodegeneration in brains of infected dogs. Cryptococcus neoformans (C. neoformans) and canine distemper virus (CDV; to a lesser extent) may cross the BBB via the ‘Trojan horse’ mechanism that comprise infection of macrophages capable of crossing the BBB and causing meningitis or meningoencephalitis. Lipopolysaccharide from gram – bacteria can decrease P-gp activity in brain endothelial cells (BECs) and increase brain accumulation of drugs and toxins. Publication license: BioRender HO27AHU2QJ.


Figure 6.



Figure 6.

Phenobarbital levels in ABCB1 (MDR1) mutant dogs. Phenobarbital is an effective anti-seizure drug that interacts with GABA-A receptor subunits, to prolong the opening of chloride ion gates in the synaptic cleft to induce CNS depression. ABCB1 gene polymorphism hinders P-gp activity in BECs of the BBB and prevents clearance of phenobarbital from the brain to the systemic circulation. This increases the efficacy of phenobarbital in managing epileptic seizures in ABCB1 mutant dogs. Publication license: BioRender TA27AQFZ9Z.

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Grants and funding

S.G.M. is supported by the Canadian Institutes of Health Research (FDN-148368; PJT-191689) and by a Canada Research Chair (Tier 1; 2019-00386). E.B. is supported by the National Council for Scientific and Technological Development (CNPq-310489/2023-7) and the Research Support Foundation of the State of Minas Gerais (FAPEMIG; APQ-00338-18 and APQ-00099-24).

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