Distribution of extracellular tracers in perivascular spaces of the rat brain

Ichimura, Takao; Fraser, Paul A.; Cserr, Helen F.

doi:10.1016/0006-8993(91)91275-6

Cited by 199 publications

(185 citation statements)

References 19 publications

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“…88 Once in the CSF, IL-1␤ follows the CSF flow and accumulates in the subarachnoid space that is separated from cortical surface by the pial membrane. Although entry of some molecules into subpial space and cortical parenchyma from the subarachnoid space has been described, 57,88 it is generally thought that the pial membrane effectively separates subarachnoid CSF and the cortical surface. 89 Systemic cytokine signals apparently propagate through the brain by several pathways (Figure 3).…”

Section: Propagation By Diffusion Through the Csfmentioning

confidence: 99%

Cytokine signals propagate through the brain

et al. 2000

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Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF␣) are proinflammatory cytokines that are constitutively expressed in healthy, adult brain where they mediate normal neural functions such as sleep. They are neuromodulators expressed by and acting on neurons and glia. IL-1 and TNF␣ expression is upregulated in several important diseases/disorders. Upregulation of IL-1 and/or TNF␣ expression, elicited centrally or systemically, propagates through brain parenchyma following specific spatio-temporal patterns. We propose that cytokine signals propagate along neuronal projections and extracellular diffusion pathways by molecular cascades that need to be further elucidated. This elucidation is a prerequisite for better understanding of reciprocal interactions between nervous, endocrine and immune systems. Molecular Psychiatry (2000) 5, 604-615.

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Section: Propagation By Diffusion Through the Csfmentioning

confidence: 99%

Cytokine signals propagate through the brain

et al. 2000

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“…Studies conducted by Weed (1914) [186] implied that increased intracranial/infusion pressure was required to achieve perivascular distribution of CSF-administered tracer, but subsequent work by Brierley (1950) [18] demonstrated perivascular distribution was possible with a physiological/minimal pressure increase. Later notable insights were provided by (1) Wagner (1974) [185] and Rennels (1985) [148], who showed that CSFinfused substances may be capable of reaching the PVS of capillaries, (2) Rosenberg [150] and Konsman [104], who demonstrated the involvement of the white matter as a bulk flow pathway for CSF-infused substances, (3) Patlak (1970, 1975) [111,135], Rosenberg (1980) [150], Ghersi-Egea (1996) [68], and Proescholdt (2000) [142], who performed experiments where the penetration of CSFinfused tracers across the brain-CSF interfaces appeared consistent with diffusive transport, and (4) Krisch (1983Krisch ( , 1984 [107,108] and Ichimura (1991) [88], who demonstrated communication between the ECS, PVS, subpial space, and subarachnoid trabeculae core following CSF infusion of tracer. It must be noted that the group of Weller and Carare have interpreted a number of their own more recent studies injecting tracers into the brain parenchyma as suggesting outward directed flow of ISF/solutes primarily confined to the capillary basal lamina and the smooth muscle basement membrane (tunica media) of arterioles/ arteries [24,120], a process they have termed an 'intramural peri-arterial drainage' pathway [48,58].…”

Section: Blood Vessels and The Perivascular Spacementioning

confidence: 99%

“…While certain aspects of the Rennels work were questioned in the decade after their publication [88], the past 5 years have witnessed a dramatically renewed interest in a possible circulation of CSF and CSF-borne tracers along perivascular spaces with relevance for CSF-ISF exchange, initially stimulated by new work from Nedergaard and colleagues [91].…”

Section: Blood Vessels and The Perivascular Spacementioning

confidence: 99%

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

et al. 2018

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Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K + , Ca 2+ , and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or 'glymphatic' system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the 'glymphatic' hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF-ISF exchange and drainage. We also consider the extent to which CSF-ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true 'circulation', but, at the least, suggests a comprehensive re-evaluation of the previously proposed 'glymphatic' concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.

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“…Soluble antigen will diffuse from the brain parenchyma to the ventricles, will be taken up by DCs, which migrate to the cervical lymph nodes, and will initiate an immune response (12)(13)(14). However, large particulate antigens are unable to diffuse out of the brain parenchyma.…”

mentioning

confidence: 99%

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

Larocque¹,

Sanderson²,

Bergeron³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Soluble antigens diffuse out of the brain and can thus stimulate a systemic immune response, whereas particulate antigens (from infectious agents or tumor cells) remain within brain tissue, thus failing to stimulate a systemic immune response. Immune privilege describes how the immune system responds to particulate antigens localized selectively within the brain parenchyma. We believe this immune privilege is caused by the absence of antigen presenting dendritic cells from the brain. We tested the prediction that expression of fms-like tyrosine kinase ligand 3 (Flt3L) in the brain will recruit dendritic cells and induce a systemic immune response against exogenous influenza hemagglutinin in BALB/c mice. Coexpression of Flt3L with HA in the brain parenchyma induced a robust systemic anti-HA immune response, and a small response against myelin basic protein and proteolipid protein epitopes. Depletion of CD4 + CD25+ regulatory T cells (Tregs) enhanced both responses. To investigate the autoimmune impact of these immune responses, we characterized the neuropathological and behavioral consequences of intraparenchymal injections of Flt3L and HA in BALB/c and C57BL/6 mice. T cell infiltration in the forebrain was time and strain dependent, and increased in animals treated with Flt3L and depleted of Tregs; however, we failed to detect widespread defects in myelination throughout the forebrain or spinal cord. Results of behavioral tests were all normal. These results demonstrate that Flt3L overcomes the brain's immune privilege, and supports the clinical development of Flt3L as an adjuvant to stimulate clinically effective immune responses against brain neo-antigens, for example, those associated with brain tumors.immune response | dendritic cells | influenza hemagglutinin | regulatory T cells | perivascular cuffs

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Distribution of extracellular tracers in perivascular spaces of the rat brain

Cited by 199 publications

References 19 publications

Cytokine signals propagate through the brain

Cytokine signals propagate through the brain

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology

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