Self-injurious behaviours in rhesus macaques: Potential glial mechanisms.

BACKGROUND: Self-injurious behaviour (SIB) can be classified as intentional, direct injuring of body tissue usually without suicidal intent. In its non-suicidal form it is commonly seen as a clinical sign of borderline personality disorder, autism, PTSD, depression, and anxiety affecting a wide range of ages and conditions. In rhesus macaques SIB is most commonly manifested through hair plucking, self-biting, self-hitting, and head banging. SIB in the form of self-biting is observed in approximately 5-15% of individually housed monkeys. Recently, glial cells are becoming recognised as key players in regulating behaviours. METHOD: The goal of this study was to determine the role of glial activation, including astrocytes, in macaques that had displayed SIB. To this end, we performed immunohistochemistry and next generation sequence of brain tissues from rhesus macaques with SIB. RESULTS: Our studies showed increased vimentin, but not nestin, expression on astrocytes of macaques displaying SIB. Initial RNA Seq analyses indicate activation of pathways involved in tissue remodelling, neuroinflammation and cAMP signalling. CONCLUSIONS: Glia are most probably activated in primates with self-injury, and are therefore potential novel targets for therapeutics.

Contributions of Nonhuman Primates to Research on Aging.

Aging is the biological process of declining physiologic function associated with increasing mortality rate during advancing age. Humans and higher nonhuman primates exhibit unusually longer average life spans as compared with mammals of similar body mass. Furthermore, the population of humans worldwide is growing older as a result of improvements in public health, social services, and health care systems. Comparative studies among a wide range of organisms that include nonhuman primates contribute greatly to our understanding about the basic mechanisms of aging. Based on their genetic and physiologic relatedness to humans, nonhuman primates are especially important for better understanding processes of aging unique to primates, as well as for testing intervention strategies to improve healthy aging and to treat diseases and disabilities in older people. Rhesus and cynomolgus macaques are the predominant monkeys used in studies on aging, but research with lower nonhuman primate species is increasing. One of the priority topics of research about aging in nonhuman primates involves neurologic changes associated with cognitive decline and neurodegenerative diseases. Additional areas of research include osteoporosis, reproductive decline, caloric restriction, and their mimetics, as well as immune senescence and chronic inflammation that affect vaccine efficacy and resistance to infections and cancer. The purpose of this review is to highlight the findings from nonhuman primate research that contribute to our understanding about aging and health span in humans.

S100ß as a novel and accessible indicator for the presence of monocyte-driven encephalitis in AIDS.

AIMS: The pathogenesis of human/simian immunodeficiency virus encephalitis (HIVE/SIVE) remains incompletely understood, but is associated with alterations in the blood-brain barrier. At present, it is not possible to easily determine if an individual has HIVE/SIVE before post mortem examination. METHODS: We have examined serum levels of the astroglial protein S100ß in SIV-infected macaques and show that it can be used to determine which animals have SIVE. We also checked for correlations with inflammatory markers such as CCL2/MCP-1, IL-6 and C-reactive protein. RESULTS: We found that increased S100ß protein in serum correlated with decreased expression of the tight junction protein zonula occludens-1 on brain microvessels. Furthermore, the decrease in zonula occludens-1 expression was spatially related to SIVE lesions and perivascular deposition of plasma fibrinogen. There was no correlation between encephalitis and plasma levels of IL-6, MCP-1/CCL2 or C-reactive protein. CONCLUSIONS: Together, these data indicate that SIVE lesions are associated with vascular leakage that can be determined by S100ß protein in the periphery. The ability to simply monitor the presence of SIVE will greatly facilitate studies of the neuropathogenesis of AIDS.

Simian immunodeficiency virus disrupts extended lengths of the blood--brain barrier.

It is known that there is disruption of the blood-brain barrier during terminal AIDS encephalitis in both human immunodeficiency virus (HIV)-infected humans and simian immunodeficiency virus (SIV)-infected rhesus macaques. Much, although by no means all, of the neuropathological findings of HIV and SIV infection involves accumulation of monocytes/macrophages that have likely crossed the blood-brain barrier (BBB). There is no convincing, rigorous, demonstration of HIV (or SIV) infecting endothelial cells in vivo. However, this is not to say that HIV infection would not have any effects on the physiology of microvascular brain endothelial cells. Because of the elaborate nature of cerebral microvessels, previous studies of cerebral endothelial cells have been constrained by sectioning artifacts. Examination of freshly isolated cerebral microvessels allows investigation of extended lengths of vessels (>150 mum) without sectioning artifacts. These studies determine the changes in the expression of the tight junction protein zo-1 protein on the endothelial cells of cerebral capillaries at terminal acquired immune deficiency syndrome, demonstrating that there is a decreased expression of zo-1 protein over extended lengths of microvessels.

Activation of the blood-brain barrier by SIV (simian immunodeficiency virus) requires cell-associated virus and is not restricted to endothelial cell activation.

The primary cell infected during acute HIV neuropathogenesis is the monocyte-derived macrophage. We have demonstrated that there is activation of the BBB (blood-brain barrier) during acute viral infection and at terminal AIDS. However, it has never been determined if there is a requirement for the virus to be carried through the BBB or how these Trojan horses would be induced to cross the BBB. We added SIVmac251-infected (SIV is simian immunodeficiency virus) mononuclear cells (and their supernatants) to the luminal or abluminal compartment of our BBB model. There was activation of both sides of the BBB model, only if viral-infected cells were added to the luminal compartment, as opposed to the addition of cell-free supernatants. This suggests that cell-associated virus is essential for the activation of the BBB. This, in turn, would be expected to lead to further infiltration of cells capable of viral infection. VCAM-1 (vascular cell adhesion molecule 1) staining revealed, for the first time, that there is an absolute requirement for virally infected cells, and not just the presence of virus for the activation of the BBB.

Rhesus macaque brain microvessel endothelial cells behave in a manner phenotypically distinct from umbilical vein endothelial cells.

Activation of endothelium is a critical step in leukocyte recruitment to the CNS and in development of neurological diseases, such as HIV-associated dementia. Due to limited availability of early disease course data, it is important to develop in vitro models of the blood-brain barrier (BBB) that can be used to address these early events. No such model of the BBB has been established for the macaque. Here, we characterize rhesus microvascular brain endothelial cells (MBEC), comparing them with rhesus umbilical vein endothelial cells (RUVEC), and discuss their suitability for future use in developing in vitro models of simian immunodeficiency virus (SIV) neuropathogenesis. We conclude that MBEC are distinct from RUVEC with respect to growth characteristics, culture requirements, morphology and expression of surface molecules important for leukocyte adhesion and immune activation.

Macaques with rapid disease progression and simian immunodeficiency virus encephalitis have a unique cytokine profile in peripheral lymphoid tissues.

The influence of host cytokine response on viral load, disease progression, and neurologic lesions was investigated in the simian immunodeficiency virus (SIV)-infected macaque model of AIDS. Cytokine gene expression (interleukin-1beta [IL-1beta], IL-2, IL-6, IL-10, gamma interferon [IFN-gamma], and tumor necrosis factor alpha [TNF-alpha]) and viral loads were evaluated by semiquantitative reverse transcription-PCR in lymph nodes of 5 control animals and 28 animals infected with SIVmac251 at the terminal stages of AIDS. Infected animals showed higher expression of IFN-gamma, IL-6, and IL-10 mRNAs compared with controls. Levels of all cytokines were comparable between animals with rapid (survival, <200 days) or slow/normal (survival, >200 days) disease progression. However, among rapid progressors, the eight animals with SIV encephalitis had a unique cytokine profile (increased IL-2, IL-6, and IFN-gamma) that was associated with higher viral loads. These observations provide evidence that host cytokine responses may influence SIV neuropathogenesis independent of disease progression.

Thymosin beta 4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids.

The possibility that glucocorticoids upregulate the expression of anti-inflammatory mediators is an exciting prospect for therapy in inflammatory diseases, because these molecules could give the therapeutic benefits of steroids without toxic side effects. Supernatants from monocytes and macrophages cultured in the presence of glucocorticoids increase the dispersion of neutrophils from a cell pellet in the capillary tube migration assay. This supernatant factor, unlike other neutrophil agonists, promotes dispersive locomotion of neutrophils at uniform concentration, lowers their adhesion to endothelial cells, inhibits their chemotactic response to fMLP and induces distinctive morphological changes. Here we show that thymosin beta4 sulfoxide is generated by monocytes in the presence of glucocorticoids and acts as a signal to inhibit an inflammatory response. In vitro, thymosin beta4 sulfoxide inhibited neutrophil chemotaxis, and in vivo, the oxidized peptide, but not the native form, was a potent inhibitor of carrageenin-induced edema in the mouse paw. Thymosin beta4 is unique, because oxidation attenuates its intracellular G-actin sequestering activity, but greatly enhances its extracellular signaling properties. This description of methionine oxidation conferring extracellular function on a cytosolic protein may have far-reaching implications for future strategies of anti-inflammatory therapy.

AY-31,906, a novel high ceiling diuretic: characterization of its relative potassium-sparing actions in rats and dogs.

AY-31,906, exo-2-amino-4-[(bicyclo[2.2.1]hept-2-yl)amino-N-[[1- methylethyl)amino]carbonyl]-5-pyrimidinesulfonamide, exhibited potent diuretic and natriuretic activity in rats and dogs. After p.o. administration, AY-31,906 was 1.5- and 12.3-times more potent as a natriuretic than furosemide in rats and dogs, respectively, whereas it was 0.5- and 6.1-times as potent after i.v. administration. The maximum natriuretic effect of AY-31,906 in both species was similar to that observed with furosemide. At equiactive natriuretic p.o. doses in both species, AY-31,906 produced a greater increase in the urinary ratio of Na/K than furosemide, indicating a relative potassium-sparing effect. AY-31,906 produced significant increases in the fractional excretion of sodium and chloride in dogs at a dose that produced no statistically significant changes in the fractional excretion of potassium, glomerular filtration rate or renal plasma flow. After p.o. administration, the onset of activity of AY-31,906 occurred within the 1st hr in both rats and dogs and preliminary data demonstrated that the activity lasted for approximately 2 hr in rats and 4 hr in dogs. Clearance studies in conscious dogs suggest that AY-31,906 inhibited electrolyte reabsorption in the ascending limb of the loop of Henle and, unlike furosemide, AY-31,906 had no activity at the proximal tubule. These results indicate that AY-31,906 is a potent, high ceiling diuretic with relative potassium-sparing properties. The compound is well absorbed after p.o. administration with diuretic activity occurring in the 1st hr.

Rapid onset of vascular wall protein synthesis with increase in lability of blood pressure in rabbits.

1. Structural and functional changes resulting from baroreceptor denervation were studied in rabbits 4 days after surgery. 2. After section of the aortic and carotid sinus nerves, arterial pressure was characteristically labile although the mean pressures were not significantly different from those of control animals. 3. The responsiveness of isolated ear arteries and cephalic veins from deafferented animals to noradrenaline and electrical stimulation of their sympathetic innervation was similar in both groups. 4. Neuronal uptake of noradrenaline into arterial tissue was similar in both groups, although uptake into the cephalic veins of deafferented animals was less than in the control group. 5. [3H]Thymidine uptake, an index of DNA synthesis, was similar in both groups, radioautography revealing no difference in smooth muscle cell labelling. 6. Uptake of [3H]proline, an indicator of protein synthesis, by aorta, ear, brachial, basilar and renal arteries from deafferented animals was greater than in control animals. 7. Baroreceptor denervation altered protein metabolism in the arterial wall.

The influence of an extraneuronal compartment on the relaxation of the cat nictitating membrane in vivo.

1 Contractions of the cat nictitating membrane were elicited on stimulation of the internal carotid nerve, and the effects were studied of desipramine and two inhibitors of catechol-O-methyltransferase, U-0521 and pyrogallol, on the subsequent relaxation of the muscle. 2 The relaxation of the nictitating membrane occurred in at least two phases. The late phase of relaxation was prolonged after increase in the period of nerve stimulation and the duration of this phase was further prolonged after treatment with pyrogallol. 3 After inhibition of neuronal uptake of noradrenaline with desipramine both the early and late phases of relaxation were increased in duration, and subsequent administration of pyrogallol or U-0521 caused a further increase in the duration of the late phase of relaxation. 4 The results suggest that the late phase of relaxation of the nictitating membrane is influenced by efflux of noradrenaline from an extraneuronal pool.

Relaxation of smooth muscle following contraction elicited by sympathetic nerve stimulation in vivo.

1. A method for studying in vivo the process of neuroeffector transmission in the nictitating membrane and nasal blood vessels of the cat is described. 2. Administration of desmethylimipramine or cocaine caused increases in both the amplitude and duration of the nasal and membrane responses which may be explained by inhibition of neuronal uptake of noradrenaline. 3. Phenoxybenzamine depressed the responses to nerve stimulation, but had little effect on the relationship between response amplitude and rate of recovery. 4. The relationship between response amplitude and rate of recovery is discussed and related to the sigmoid shape of a log concentration-response curve.