Regulation of brain water permeability by centrally-released vasopressin

Oxytocin (OXT) and vasopressin (AVP) are related neuropeptides that exert a wide range of effects on general health, homeostasis, development, reproduction, adaptability, cognition, social and nonsocial behaviors. The two peptides are mainly of hypothalamic origin and execute their peripheral and central physiological roles via OXT and AVP receptors, which are members of the G protein-coupled receptor family. These receptors, largely distributed in the body, are abundantly expressed in the hippocampus, a brain region particularly vulnerable to stress exposure and various lesions. OXT and AVP have important roles in the hippocampus, by modulating important processes like neuronal excitability, network oscillatory activity, synaptic plasticity, and social recognition memory. This chapter includes an overview regarding OXT and AVP structure, synthesis, receptor distribution, and functions, focusing on their relationship with the hippocampus and mechanisms by which they influence hippocampal activity. Brief information regarding hippocampal structure and susceptibility to lesions is also provided. The roles of OXT and AVP in neurodevelopment and adult central nervous system function and disorders are highlighted, discussing their potential use as targeted therapeutic tools in neuropsychiatric diseases.

Pharmacological MRI (phMRI) studies seek to capture changes in brain haemodynamics in response to a drug. This provides a methodological platform for the evaluation of novel therapeutics, and when applied to disease states, may provide diagnostic or mechanistic information pertaining to common brain disorders such as dementia. Changes to brain perfusion and blood-cerebrospinal fluid barrier (BCSFB) function can be probed, non-invasively, by arterial spin labelling (ASL) and blood-cerebrospinal fluid barrier arterial spin labelling (BCSFB-ASL) MRI respectively. Here, we introduce a method for simultaneous recording of pharmacological perturbation of brain perfusion and BCSFB function using interleaved echo-time ASL, applied to the anesthetized mouse brain. Using this approach, we capture an exclusive decrease in BCSFB-mediated delivery of arterial blood water to ventricular CSF, following anti-diuretic hormone, vasopressin, administration. The commonly used vasodilatory agent, CO₂, induced similar increases (~21%) in both cortical perfusion and the BCSFB-ASL signal. Furthermore, we present evidence that caffeine administration triggers a marked decrease in BCSFB-mediated labelled water delivery (41%), with no significant changes in cortical perfusion. Finally, we demonstrate a marked decrease in the functional response of the BCSFB to, vasopressin, in the aged vs adult brain. Together these data, the first of such kind, highlight the value of this translational approach to capture simultaneous and differential pharmacological modulation of vessel tone at the blood brain barrier and BCSFB and how this relationship may be modified in the ageing brain.

A secondary and often lethal consequence of traumatic brain injury is cellular edema that we posit is due to astrocytic swelling caused by transmembrane water fluxes augmented by vasopressin-regulated aquaporin-4 (AQP4). We therefore tested whether vasopressin 1a receptor (V1aR) inhibition would suppress astrocyte AQP4, reduce astrocytic edema, and thereby diminish TBI-induced edematous changes. V1aR inhibition by SR49059 significantly reduced brain edema after cortical contusion injury (CCI) in rat 5 h post-injury. Injured-hemisphere brain water content (n=6 animals/group) and astrocytic area (n=3/group) were significantly higher in CCI-vehicle (80.5±0.3%; 18.0±1.4 µm²) versus sham groups (78.3±0.1%; 9.5±0.9 µm²), and SR49059 blunted CCI-induced increases in brain edema (79.0±0.2%; 9.4±0.8 µm²). CCI significantly up-regulated GFAP, V1aR and AQP4 protein levels and SR49059 suppressed injury induced up regulation (n=6/group). In CCI-vehicle, sham and CCI-SR49059 groups, GFAP was 1.58±0.04, 0.47±0.02, and 0.81±0.03, respectively; V1aR was 1.00±0.06, 0.45±0.05, and 0.46±0.09; and AQP4 was 2.03±0.34, 0.49±0.04, and 0.92±0.22. Confocal immunohistochemistry gave analogous results. In CCI-vehicle, sham and CCI-SR49059 groups, fluorescence intensity of GFAP was 349±38, 56±5, and 244±30, respectively, V1aR was 601±71, 117.8±14, and 390±76, and AQP4 was 818±117, 158±5, and 458±55 (n=3/group). The results support that edema was predominantly cellular following CCI and documented that V1aR inhibition with SR49059 suppressed injury-induced up regulation of GFAP, V1A and AQP4, blunting edematous changes. Our findings suggest V1aR inhibitors may be potential therapeutic tools to prevent cellular swelling and provide treatment for post-traumatic brain edema.

Aquaporin 4 (AQP4) is abundantly expressed in the perivascular glial endfeet in the central nervous system (CNS), where it is involved in the exchange of fluids between blood and brain. At this location, AQP4 contributes to the formation and/or the absorption of the brain edema that may arise following pathologies such as brain injuries, brain tumours, and cerebral ischemia. As vasopressin and its G-protein-coupled receptor (V1_aR) have been shown to affect the outcome of brain edema, we have investigated the regulatory interaction between AQP4 and V1_aR by heterologous expression in Xenopus laevis oocytes. The water permeability of AQP4/V1_aR-expressing oocytes was reduced in a vasopressin-dependent manner, as a result of V1_aR-dependent internalization of AQP4. Vasopressin-dependent internalization was not observed in AQP9/V1_aR-expressing oocytes. The regulatory interaction between AQP4 and V1_aR involves protein kinase C (PKC) activation and is reduced upon mutation of Ser¹⁸⁰ on AQP4 to an alanine. Thus, the present study demonstrates at the molecular level a functional link between the vasopressin receptor V1_aR and AQP4. This functional interaction between AQP4 and V1_aR may prove to be a potential therapeutic target in the prevention and treatment of brain edema.

A unique feature of cerebral endothelial cells (CECs) is the formation of the blood–brain barrier (BBB), which contributes to the stability of the brain microenvironment. CECs are capable of producing several substances mediating endothelium-dependent vasorelaxation or vasoconstriction, regulating BBB permeability, and participating in the regulation of cell–cell interactions during inflammatory and immunological processes. The chemical nature of these mediators produced by CECs ranges from gaseous anorganic molecules (e.g. nitric oxide) through lipid mediators (e.g. prostaglandins) to peptides. Peptide mediators are a large and diverse family of bioactive molecules which can elicit multiple effects on cerebral endothelial functions. In this review, we summarize current knowledge of peptide mediators produced by CECs, such as adrenomedullin, angiotensin, endothelin and several others and their role in the regulation of BBB functions.

The Wistar Audiogenic Rat (WAR) is a genetic model of reflex epilepsy with seizures induced by high-intensity sound stimulation (120 dB SPL). In spite of the known neural substrates involved in WAR seizure phenotype, neuroendocrine hypothalamic neurons were never investigated. In this work, AVP immunohistochemistry in the hypothalamus and radioimmunoassay (RIA) in plasma and in hypothalamic and hypophysial tissues were performed on both controls and WARs in order to evaluate the dynamics of AVP release due to seizure induction. Susceptible animals (WARs) displayed at least tonic–clonic convulsions followed by clonic spasms, while resistant Wistar rats (R) had no convulsive behavior. Animals were sacrificed at 3 instances: basal condition (without stimulus) and at 3 and 10 min after sound stimulation. For the immunohistochemistry AVP study, brains were harvested and processed by the avidin–biotin–peroxidase detection method. Optic densitometry was used for quantifying AVP labeling in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. SON presented higher densitometry levels (%D—relative to background) for both WARs and R when compared to PVN. Nevertheless, both nuclei presented a marked decrease, referenced to basal levels, in %D for WARs at 3 min (~35%) against a discrete change for R (~90%). RIA results were significantly higher in the hypophysis of WARs when compared to R rats, at 3 min. Also, at 3 min, plasma AVP in WARs (89.32 ± 24.81 pg/mL) were higher than in R (12.01 ± 2.39 pg/mL). We conclude, based on the AVP releasing profiles, that vasopressinergic hypothalamic neurons are recruited during the audiogenic seizure of WARs.