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Review
. 2010;20 Suppl 1(Suppl 1):S51-62.
doi: 10.3233/JAD-2010-091261.

Caffeine and the control of cerebral hemodynamics

Affiliations
Review

Caffeine and the control of cerebral hemodynamics

Dale A Pelligrino et al. J Alzheimers Dis. 2010.

Abstract

While the influence of caffeine on the regulation of brain perfusion has been the subject of multiple publications, the mechanisms involved in that regulation remain unclear. To some extent, that uncertainty is a function of a complex interplay of processes arising from multiple targets of caffeine located on a variety of different cells, many of which have influence, either directly or indirectly, on cerebral vascular smooth muscle tone. Adding to that complexity are the target-specific functional changes that may occur when comparing acute and chronic caffeine exposure. In the present review, we discuss some of the mechanisms behind caffeine influences on cerebrovascular function. The major effects of caffeine on the cerebral circulation can largely be ascribed to its inhibitory effects on adenosine receptors. Herein, we focus mostly on the A1, A2A, and A2B subtypes located in cells comprising the neurovascular unit (neurons, astrocytes, vascular smooth muscle); their roles in the coupling of increased neuronal (synaptic) activity to vasodilation; how caffeine, through blockade of these receptors, may interfere with the "neurovascular coupling" process; and receptor-linked changes that may occur in cerebrovascular regulation when comparing acute to chronic caffeine intake.

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Figures

Fig. 1
Fig. 1
The neurovascular unit (represented by a synaptic, astrocytic, and vascular component) and the role of adenosine (ADO), via its receptors, in the coupling of enhanced neural activity to arteriolar vascular smooth muscle (VSM) relaxation. Synaptic Component. Increased axonal activity is characterized by enhanced Ca2+ entry and accumulation in presynaptic nerve terminals, promoting a Ca2+-dependent vesicular release of, for example, glutamate (glu) and ATP from the presynaptic terminal into the synaptic cleftformula image. The released ATP can be rapidly converted to adenosine (ADO) via ectonucleotidasesformula image. The increased ADO can engage A1 and A2A receptors on pre- and post-synaptic membranes, and it can interact with A2A and A2B receptors on adjacent astrocytes (see below). Although A1 receptors may be expressed on astrocytes and blood vessels, in the Fig. 1 model, those sites are not assigned any functional significance (see Table 1). The glutamate released from the presynaptic terminal can effect post-synaptic activation via engaging metabotropic (mGluR) or ionotropic (NMDA and AMPA) receptors on post-synaptic dendritesformula image. Post-synaptic activation of A1 and A2A receptors has been associated with repression of glutamate-linked post-synaptic function [22]. This could act as a “brake” on trans-synaptic signalingformula image. The patterns of A1 and A2A receptor expression, as well as the neurotransmitters they modulate, vary among brain structures. Based upon information obtained from cerebrocortical synaptosomes (where evidence indicates the presence of both A1 and A2A receptor-mediated modulation of glutamate release [32,33]), the model depicted in Fig. 1 (and Fig. 2) could be taken to represent cerebral cortex. The figure depicts the presence of A1 and A2A receptors in close association with one another in the presynaptic nerve ending. This “heteromeric” arrangement represents one of several possibilities, including scenarios where the A1 or A2A receptor subtype predominates. In the heteromeric arrangement, it has been postulated that the Gs-linked A2A receptor not only will activate adenylyl cyclase (AC), but also, via a PKA-independent mechanism [32,33], prevent the Gi/o-linked A1 receptor from inhibiting AC, especially under conditions of increased neuronal activity and ADO availability [35]formula image. One consequence of this will be a PKA-driven increased Ca2+ influx at the presynaptic membrane, overcoming A1 receptor-linked depression of voltage-dependent Ca2+ entry [33], thereby potentiating Ca2+-dependent glutamate/ATP release and extracellular ADO generationformula image. Astrocytic Component. The released ATP and glutamate can interact with astrocyte metabotropic P2Y receptorsformula image and mGluR'sformula image, respectively, leading to mobilization of Ca2+ from intracellular storage sites within astrocytesformula image. In addition, the increased presence of ADO, arising from the released ATP, activates A2A receptors on astrocytes leading to cAMP/PKA-dependent mobilization of intracellular Ca2+ from cellular storesformula image. Adenosine interaction with astrocytic A2A receptors also can contribute to blockade of the astrocytic glutamate import protein, GLT-1formula image; and promote Ca2+-dependentformula image enhancement of glutamate effluxformula image. This should result in further elevations in glutamate levels in the synaptic cleft, as well as contributing to the astrocytic “Ca2+ wave”. The figure also speculates that a PKA-linked “boost” to the astrocytic Ca2+ mobilizationformula image may arise from ADO binding to Gs-linked A2B receptorsformula image. The “wave” of Ca2+ generated by the combined influences of glutamatergic, purinergic P2Y, and adenosinergic mechanisms will ultimately promote ATP release from astrocytes, including remote sitesformula image. ATP represents an important signaling molecule in astrocytes. It arises from cellular glucose and O2 metabolism and can diffuse (along with Ca2+) from astrocyte to astrocyte through gap junctionsformula image. Additionally, ATP represents perhaps the most important molecule involved in inter-astrocytic communication. Thus, Ca2+-dependent release of ATP from one astrocyte interacts with P2Y receptors on adjacent astrocytes, contributing to the spread of the Ca2+ wave. Arteriolar Component. The release of ATP in the vicinity of arterioles is likely to result in rapid formation of ADOformula image and interactions with smooth muscle A2 receptors. There is little doubt that cerebral arterioles are well-endowed with A2 receptors. Both A2 subtypes are likely to be present on cerebral resistance vessels; although the literature seems to favor the A2A receptor, especially in intraparenchymal and pial arterioles [24,50]. This is reflected in the figure. Principally, A2 activation generates cAMPformula image, which is not only capable of activating PKA, but cGMP-dependent protein kinase (PKG) as well [46,70]formula image. The increased kinase function is associated with phosphorylation and opening of K+ channelsformula image, leading to smooth muscle cell hyperpolarization (↓Vm). This lowers intracellular Ca2+ levels through a reduction in Ca2+ influx via voltage-operated Ca2+ channels. Elevated PKA/PKG function also is accompanied by a reduction in the Ca2+-sensitivity of contractile proteins (e.g., myosinformula image). The combination of reduced VSM Ca2+ levels and diminished sensitivity to Ca2+ leads to relaxation. See text for further discussion and additional citations.
Fig. 2
Fig. 2
Scheme depicting diminished neurovascular coupling during acute caffeine exposure. There are several potential manifestations related to caffeine restriction of ADO interactions with A1 and A2A receptors in presynaptic nerve endings. The net effect of that “multi-receptor blockade” on glutamate (and ATP) release during increased synaptic activity depends on the A1/A2A configuration. In an A1 receptor-dominant presynaptic configuration, the presence of caffeine should remove the postulated A1 receptor-related block of voltage-dependent Ca2+ entry (e.g. [71]), thus increasing Ca2+-mediated glutamate and ATP release. In an A2A receptor-dominant presynaptic scenario (probably the least likely), caffeine blockade is likely to attenuate glutamate release during states of increased neuronal activity. In Fig. 2, the heteromeric A1/A2A receptor arrangement is representedformula image. Although precise predictions are not possible, caffeine-related blockade of both receptors might be associated with modest or no changes in activity-evoked glutamate and ATP releaseformula image. Further reductions in glutamate presence in the synaptic cleft may arise from caffeine blockade of astrocytic A2A receptorsformula image – leading to disinhibition of GLT-1 (permitting greater uptake of glutamate from the synaptic cleft)formula image and diminished A2A receptor-mediated Ca2+-dependent glutamate effluxformula image. A net reduction in glutamate levels in the synaptic cleft could restrict the generation of glutamate receptor-mediated post-synaptic activationformula image. Yet, the presence of caffeine will also prevent ADO-linked post-synaptic depression mediated through activation of A1 and A2A receptorsformula image. This may permit some post-synaptic activation to occur. Moreover, caffeine blockade of astrocytic A2A and A2B receptorsformula imageformula image, along with the diminished contributions from metabotropic purinergic and glutamatergic receptors (arising from reduced extracellular ATP and glutamate levelsformula image), a large reduction in the capacity to generate a Ca2+ wave might be expectedformula image, resulting in less ADO being “presented” to VSM cellsformula image. The diminished ADO exposure, combined with caffeine blockade of VSM A receptorsformula image, leaves little capacity remaining for ADO-mediated vasodilation. The potentially diminished capacity to effect “remote” increases in extracellular ADO could also interfere with heterosynaptic influences (see Fig. 1 legend); although the lack of relevant information does not permit any further discussion of this matter. The above speculation provides some (although not the only) possible explanations for the finding that acute caffeine administration profoundly attenuates the in vivo dilation of pial arteriolesformula image accompanying somatosensory activation in rats [54].

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