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PubMed1983

Platelet function after shipment of room temperature platelet concentrates.

Platelet concentrates stored for 48 or 72 h were shipped up to 10 h at 22 or 4 degrees C. Thereafter platelet function was compared with platelet concentrates stored under optimal blood bank conditions with continuous agitation and strict temperature control. Platelet function measured by hypotonic shock response, aggregation and serotonin uptake is better maintained at 22 than at 4 degrees C. The only difference between shipping and continuous agitation is seen in the hypotonic shock response after a total storage time of 72 h. Shipped platelets showed a marked drop in hypotonic-shock response. The data indicate that shipment of platelet concentrates does not significantly impair platelet function.

Blood Platelets↗
PubMed1985

Structure and function of platelet membrane glycoproteins Ib and V. Effects of leukocyte elastase and other proteases on platelets response to von Willebrand factor and thrombin.

Treatment of platelets with human leukocyte elastase causes a rapid loss in response to von Willebrand factor and a biphasic loss in response to thrombin, first rapid then more slowly. The rapid phase corresponds to cleavage of a 45-kDa glycopeptide from the extracellular end of membrane glycoprotein GPIb. Longer treatment removes 80-kDa and 90-kDa glycopeptides and a glycopeptide corresponding to the major part of GPV. The 45-kDa and 90-kDa species could be obtained by elastase treatment of glycocalicin, the major proteolytic cleavage product of GPIb. Polyclonal rabbit antibodies against the purified 45-kDa glycopeptide had the same effect on the action of von Willebrand factor and thrombin on platelets as cleavage of GPIb by elastase. These results indicate that both the von Willebrand factor and thrombin binding sites on GPIb are located in the same region on the outside of the molecule. Thrombin activation of platelets involves at least two receptors, one on the 45-kDa glycopeptide, which when occupied causes an increase in the speed of response of the platelets to the cleavage of the second. GPV, a candidate for the second receptor, is a hydrophobic glycoprotein that is cleaved from the platelet membrane by several proteases. Proteases that do not activate platelets but degrade the second receptor remove larger fragments from GPV than do proteases such as thrombin or trypsin which activate platelets.

Blood Platelets↗
PubMed1992

Two different sites of action for platelet activating factor and 1-O-alkyl-2-O-methyl-sn-glycero-3-phosphocholine on platelets and leukemic cells.

2-O-Methyl analogs of platelet activating factor (PAF) are potent anticancer agents. The sites of action and mechanisms of cell toxicity of these agents are as yet unknown. To better understand the mode of action of this class of anticancer agents, we examined the ability of 1-O-hexadecyl-2-acetylglycero-3-phosphocholine with the S or R configuration at C2 ((R)-PAF and (S)-PAF) and 1-O-hexadecyl-2-methoxyglycero-3-phosphocholine with the S or R configuration at C2 ((R)-ET-16-OCH3-GPC and (S)-ET-16-OCH3-GPC) to induce rabbit platelet aggregation and to inhibit [3H]thymidine uptake into WEHI-3B cells, HL-60 cells, and normal blood lymphocytes. The four chiral ether-linked lipids caused aggregation of rabbit platelets with the following order of potency: (R)-PAF greater than (S)-PAF greater than (R)-ET-16-OCH3-GPC greater than (S)-ET-16-OCH3-GPC; the EC50 values were 1 pM, 50 nM, 1 microM, and 50 microM, respectively. The cytotoxic effects of these ether lipids in leukemic cells was in reverse order to that observed for aggregation of platelets. The order of potency for inhibition of [3H]thymidine uptake by WEHI-3B and HL-60 cells was (R)-ET-16-OCH3-GPC = (S)-ET-16-OCH3-GPC greater than (S)-PAF greater than (R)-PAF; the EC50 values were 2, 2, 15, and greater than 40 microM, respectively. PAF antagonists (WEB 2086, CV 3988, triazolam, and SRI 63,441) blocked the action of the four ether lipids on platelets, while SRI 63,441 blocked the antineoplastic activity of the ether lipids on WEHI-3B and HL-60 cells. None of the four lipids was able to kill normal lymphocytes significantly. Scatchard analysis of PAF receptor binding revealed that HL-60 and WEHI-3B cells, which are sensitive to the cytotoxic action of ether-linked lipids, do not possess PAF receptors, whereas both normal lymphocytes and platelets do possess a PAF receptor. The present data indicate that the cytotoxic action of antineoplastic ether-linked lipids does not involve the PAF receptor. The protective role of SRI 63,441 in blocking the proaggregatory activity of the ether lipids in rabbit platelets involves PAF receptor, but cytotoxic activity against WEHI-3B and HL-60 cells does not result from its ability to act as a PAF antagonist.

Animals↗
PubMed2002

Functional significance of adenosine 5'-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ibalpha induced by conditions of high shear rate.

BACKGROUND: The role of the adenosine 5'-diphosphate receptor P2Y(12) in platelet activation initiated by the von Willebrand factor (VWF)-GP Ibalpha interaction under high shear rate was investigated. METHODS AND RESULTS: Blood samples were obtained from 11 donors. Shear-induced platelet aggregation was detected by optically modified cone-plate viscometer. Shear-induced VWF binding, P-selectin expression, and microparticle release were detected by flow cytometry. Platelet interaction with immobilized VWF was also investigated by parallel-plate flow chamber equipped with epifluorescent videomicroscopy. Effects of a selective P2Y(12) antagonist AR-C69931 MX were tested. AR-C69931 MX inhibited shear-induced platelet aggregation in a dose-dependent manner, achieving the maximum inhibition at 100 nmol/L. The extent of aggregation after exposure to a shear rate of 10 800 s(-1) for 6 minutes in the presence of 100 nmol/L AR-C69931 MX was 32.4+/-8.2% (mean+/-SD), which was significantly lower than the value in the controls of 69.7+/-9.6% (P<0.01). The inhibiting effects of AR-C69931 MX were reversed by exogenous addition of adenosine 5'-diphosphate. Shear-induced VWF binding and P-selectin surface translocation, which occurred in 4696+/-911 and 5964+/-784, respectively, of 10 000 measured platelets, was also inhibited by AR-C69931 MX (100 nmol/L) to 1948+/-528 and 2797+/-718, respectively (P=0.0018 and P=0.0009). Microparticle release was similarly inhibited. In a flow chamber experiment, firm platelet attachment on immobilized VWF was inhibited by AR-C69931 MX, whereas transient interaction was not influenced. All the above reactions were completely inhibited by blocking VWF-GP Ibalpha interaction. CONCLUSIONS: We have demonstrated that the stimulation of P2Y(12) is involved in platelet activation initiated by the binding of VWF to GP Ibalpha induced by a high shear rate.

Adenosine Diphosphate↗
PubMed1986

Role of shear rate and platelets in promoting fibrin formation on rabbit subendothelium. Studies utilizing patients with quantitative and qualitative platelet defects.

The deposition of platelets on subendothelium of rabbit aortic segments exposed to non-anticoagulated human blood increased progressively with increasing wall shear rates (50-2,600 s-1), whereas fibrin deposition decreased. Studies in normal subjects and patients with platelet disorders suggested that, under the conditions used, platelets were essential for fibrin deposition at intermediate (650 s-1) but not low (50 s-1) shear rates. Fibrin deposition was markedly diminished in a patient with Scott syndrome whose platelets have a diminished capacity to bind Factor Xa and activate Factors IX and II. In glycoprotein IIb-IIIa deficiency, fibrin deposition was normal (or somewhat increased), whereas in glycoprotein Ib deficiency the association of fibrin with platelets, but not subendothelium, was decreased. The findings indicate that platelets, perhaps through surface localization of coagulation proteins, promote fibrin deposition on subendothelium at arterial shear rates and suggest that agents directed against platelet coagulant properties could be antithrombotic.

Blood Platelet Disorders↗
PubMedDate not supplied

Enhanced platelet force development despite drug-induced inhibition of platelet aggregation in patients with thromboangiitis obliterans--two case reports.

Thromboangiitis obliterans (TAO) is a nonatherosclerotic, nonnecrotizing, nonspecific, segmental inflammatory obliterative vasculitis, characterized by decreased flow to the distal extremities and increased risk of amputation. While smoking cessation is viewed as critical to successful treatment, various therapeutic options have been employed. While many treatment regimens seek to diminish platelet function, there are relatively few studies of platelet function in this disease entity and even fewer that have offered evidence of increased platelet activity. The authors report here 2 cases of TAO in which evaluations for hypercoagulable states and of platelet function were performed. Platelet contractile force (PCF) was found to be 82% higher than a normal control in 1 TAO patient and 340% higher than normal in the second patient. This was true despite the fact that platelet aggregations confirmed suppression of aggregation by antiplatelet medications. Elevated PCF has been seen in a variety of conditions, such as coronary artery disease and diabetes mellitus, in which endothelial function is abnormal. Whether high PCF values play a role in the pathogenesis of these diseases or simply serve as markers of enhanced platelet function and/or endothelial dysfunction awaits additional evaluations.

Adult↗
PubMed1993

Inhibitory effects of a novel antiplatelet agent, E5510, on collagen-induced platelet-derived growth factor release and aggregation of human platelets in vitro.

E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, is a new anti-platelet-aggregation agent under development. We examined the inhibitory efficacy of E5510 on PDGF-release from washed human platelets. E5510 concentration-dependently inhibited collagen-induced PDGF release from human platelets. PDGF release was reduced to below the detection limit (0.47 ng/ml) by preincubation of platelets with 0.04 microM or higher concentrations of E5510. Total growth factor release from platelets was also measured by a bioassay with cultured smooth muscle cells. E5510 almost completely abolished the mitogenic effect of collagen-induced platelet releasates at concentrations of 0.04 microM or higher. Our data suggest that the release of PDGF and other growth factors was inhibited by E5510 at the same concentration that inhibited platelet aggregation.

Animals↗
PubMed1999

von Willebrand factor contained in a high purity FVIII concentrate (Fanhdi) binds to platelet glycoproteins and supports platelet adhesion to subendothelium under flow conditions.

BACKGROUND AND OBJECTIVE: There is evidence suggesting that von Willebrand factor (VWF) from high purity factor VIII concentrates could be of clinical use in the management of patients suffering from VWD. We analyzed structural and functional characteristics of VWF present in a high purity factor VIII concentrate VWFHPC (Fanhdi). The multimeric structure, the ability to bind to platelet GP Ib/IX or GP IIb/IIIa, and the capacity of VWFHPC to promote platelet adhesion on injured vessels were investigated and compared with that present in standard plasma cryoprecipitates [VWFCRYO]. DESIGN AND METHODS: Binding studies were carried out by incubating radiolabeled VWF and washed platelets, which were activated with either ristocetin (1 mg/mL; for GP Ib/IX), or thrombin (2.5 U/mL; for GP IIb/IIIa). Platelet adhesion was assessed in a perfusion system (shear rate = 800 s-1, 10 min) in which the source of VWF was added (at 0.4 or 0.8 U/mL VWF:Ag) to washed platelets and red cells suspended in a human albumin solution. The deposition of platelets onto the perfused subendothelial surface was morphometrically evaluated and expressed as percentage of surface coverage (%SC). RESULTS: The VWFHPC (152 Units VWF:RCof/mg protein; VWF:RCof/VWF:Ag = 0.97), lacked only a small proportion of high-molecular-weight multimers present in VWFCRYO. Binding affinities (Kd values, nM) of VWFHPC were similar to those of VWFCRYO (5.3 +/- 0.86 vs 5.2 +/- 0.95, for GP Ib/IX; and 11.6 +/- 2.7 vs 15.4 +/- 1.7 for GPIIb-IIIa). A slightly, though not significantly, higher binding capacity for these receptors (Bmax values, molecules/pit) was obtained for VWFHPC. The %SC in perfusions in the presence of albumin was < 10%. Addition of VWFHPC or VWFCRYO significantly increased the %SC, with values of 27.1 +/- 4.9 and 17.5 +/- 2.8%, respectively with 0.4 U/mL (p < 0.004 and p < 0.02 vs albumin); and 30.8 +/- 4.9% and 20.03 +/- 4.1%, respectively, at 0.8 U/mL (p < 0.001 and p < 0.02 vs albumin). INTERPRETATION AND CONCLUSIONS: Our data show that VWF present in the high purity FVIII concentrate Fanhdi retains the functional capacity to bind to GPs Ib/IX and IIb/IIIa and to promote platelet adhesion onto exposed subendothelium.

Albumins↗
PubMed1986

Prolonged bleeding time, reduced platelet aggregation, altered PAF-acether sensitivity and increased platelet mass are a trait of asthma and hay fever.

In a case control study 31 asymptomatic patients with asthma and/or hay fever and 31 normal controls had their bleeding time measured using the Simplate II device and venostasis. Mean bleeding time in the atopic group (527 s) was significantly prolonged compared to the controls (393 s) (p less than 0.0005). Platelet aggregation to collagen and ADP (but not to PAF-acether) was significantly depressed in the atopics. Mean circulating platelet mass was significantly greater in atopics than in the controls (p = 0.006). Stepwise multiple regression analysis showed that within the control group bleeding time was best predicted by platelet mass (p = 0.007). No such relationship was found in the atopics. However stepwise multiple regression analysis showed that bleeding time in the atopics (but not in the controls) was best predicted by PAF-acether induced platelet aggregability (p less than 0.05). In neither group was bleeding time related to collagen induced platelet thromboxane B2 production. It is hypothesised that in respiratory atopy the depressed aggregatory function of platelets is not compensated for sufficiently by an increase in platelet mass, leading to prolongation of the bleeding time. This haemostatic imbalance, whose cause remains to be established, appears to constitute a trait of atopy.

Adenosine Diphosphate↗
PubMed1995

[The relationship between P-selectin on platelet membrane and platelet function in chronic cor pulmonale].

Platelet plays an important role in thromboembolic diseases. It is demonstrated that recurrent pulmonary embolism may cause pulmonary hypertention. In recent years, P-selectin (granule membrane protein, GMP140) was found to be a surface marker for platelet activation. In order to investigate the role of platelet in chronic cor pulmonale, the changes of P-selectin on platelet membrane and its effect on platelet adhesiveness (PAdT) and platelet aggregation (PAgT) were studied. The results showed that the changes of P-selectin PAdT and PAgT in chronic cor pulmonale were significant than those in chronic pulmonary diseases and controls (P < 0.01). There was positive correlation between P-selectin and PAdT (r = 0.6831, P < 0.01) as well as PAgT (r = 0.7142, P < 0.01). The levels of von Willebrand factor (vWF) and fibrinogen (Fg) were markedly increased in chronic cor pulmonale as compared with chronic pulmonary disease and control group (P < 0.01). There was also positive correlation between vWF and PAgT (r = 0.4143, P < 0.05) as well as between Fg and PAgT (r = 0.4392, P < 0.05). It is concluded that platelet plays an important role in the pathogenesis of chronic cor pulmonale.

Aged↗
PubMed1993

Studies of thromboxane B2, platelet factor 4, and fibrinopeptide A in bleeding-time blood of patients deficient in von Willebrand factor, platelet glycoproteins Ib and IIb-IIIa, and storage granules.

The blood volumes and concentrations of thromboxane B2 (TxB2), platelet factor 4 (PF4), and fibrinopeptide A (FPA) were measured every 30 seconds in bleeding-time blood in normal subjects and in patients with idiopathic thrombocytopenic purpura (ITP), delta and alpha delta storage pool deficiency (SPD), Bernard-Soulier Syndrome (BSS), thrombasthenia (TSA), and von Willebrand's disease (vWD). Data were fitted to second-order (TxB2, PF4, and FPA) or third-order (volumes) polynomials. Average values for various parameters over fixed-time intervals were determined by numerical methods. The bleeding time was greater than 15 minutes in all patient groups and the initial bleeding, as reflected by the initial slope of the fitted blood volume curves, was increased in ITP, BSS, and SPD (delta-SPD in particular), but not in vWD and TSA. The increased values for both the initial slope and the volume of blood collected after 2 minutes in SPD suggest that vascular tone may be modulated, in part, by dense granule substances such as adenosine triphosphate (ATP) or serotonin. In TSA, uniquely, both platelet (TxB2 and PF4) and coagulation (FPA) values were increased in early bleeding samples (initial slope). In vitro studies of TxB2 production, together with previous flow studies of fibrin formation, also suggest enhanced activation and coagulant properties of thrombasthenic platelets. In other patients, reduced values of all substances at later times may reflect impaired platelet-fibrin plug formation in the high-shear regions at the ends of transected blood vessels. However, the initial slopes of the fitted curves for both TxB2 and PF4 were normal in vWD, suggesting that the early appearance of these substances may typically be from platelets that are adherent to collagen within the lower shear environment of the wound surface. The finding that FPA values were not decreased initially in any patient group, including ITP, but were decreased at later times (except for TSA), suggests that early fibrin formation occurs independently of platelets in the low-shear environment of the wound surface, whereas at later times fibrin is formed in a platelet-dependent manner in the high-shear regions at the ends of transected vessels.

Adult↗
PubMed1996

Increased platelet and coagulatory activity in peripheral atherosclerosis flow mediated platelet function is a sensitive and specific disease indicator.

The importance of flow in both athero- and thrombogenesis is well established. In peripheral arterial disease (PAD) atherosclerosis is disseminated, thrombosis risk high and systemic hemostatic derangement believed contributory. We studied platelet and coagulatory activity in PAD patients, thereby evaluating the clinical efficacy of Stagnation Point Flow Adhesio-Aggregometry (SPAA). SPAA provides real-time quantitative assessment of platelet adhesion and aggregation under convective, low-shear flow conditions. 62 nondiabetic PAD patients and 66 healthy volunteers were examined, whereby SPAA and conventional aggregometry were performed and circulating fibrinogen, fibrin monomer (FM), the fibrin degradation product D-Dimer and thrombin-antithrombin-complex (TAT) assessed. Conventional aggregometry detected no differences between patients and controls. SPAA-measured platelet function (p < 0.001), fibrinogen (p < 0.001), FM (p < 0.001), TAT (p < 0.02) and D-Dimer (p < 0.001) were significantly increased in patients and not effected by aspirin therapy. Respective sensitivity and specificity in detecting PAD was as follows: SPAA (96%/95%), fibrinogen (36%/92%), FM (46%/88%), TAT (40%/73%), D-Dimer (75%/80%). Increased platelet and coagulatory activity was verified in PAD, whereby flow-mediated platelet adhesion and aggregation proved the most sensitive and specific parameter. These findings indicate the usefulness of SPAA for delineating platelet-related disease mechanisms and evaluating therapeutic strategies to prevent platelet activation.

Antithrombin III↗
PubMed1981

Role of platelets in vasogenic brain edema. II. Contribution of platelet serotonin in brain edema.

In this study of the function of platelets after CNS injury, platelets were treated with serotonin labeled with radioactive carbon (14C) in animals subjected to a freezing lesion of the cerebrum. The distribution of platelet serotonin was measured by counting the specific activity of 14C-labeled serotonin in tissue and by autoradiography. Some of the animals were treated with RA-233, which inhibits the formation of platelet plugs after endothelial damage and the release of serotonin from platelets. Platelet serotonin accumulated near the surface of the cortex at the site of injury in all animals. More cerebral edema developed in animals treated with the platelet inhibitor than in untreated animals, probably because platelet aggregates were inhibited from forming and were not available to plug leaks in the traumatized vessels. Serotonin did not appear to facilitate the spread of edema.

Animals↗
PubMed1986

Indium 111-labeled platelet kinetic studies and platelet-associated IgG in hairy cell leukemia.

In order to study the pathogenesis of thrombocytopenia in patients with hairy cell leukemia (HCL), levels of platelet-associated IgG (PAIgG), platelet life span (MLS), and the sequestration site of autologous 111In-labeled platelets were measured in nine patients with HCL. Splenectomized patients (n = 4) had a higher platelet count (x = 122.5 X 10(9)/l; range, 80-190 X 10(9)/l) as well as higher levels of PAIgG (x = 10.7%; range, 5.8-16.9%), than nonsplenectomized patients (platelets x = 76 X 10(9)/l, range 40-100 X 10(9)/l; PAIgG x = 3.2%, range 2.2-4.2%). A normal recovery of 111In-labeled platelets was found in splenectomized patients, whereas a very low recovery was observed in the nonsplenectomized group (x = 70.2%, range, 50-82.5%, versus x = 22.4%, range, 15-28.2%). The MLS was borderline normal in all patients. The site of sequestration was the spleen in nonsplenectomized patients. The low recovery of 111In-labeled platelets in nonsplenectomized patients suggests "hypersplenism" with pooling as a major cause of thrombocytopenia, in addition to impaired thrombocytopoiesis and possible immune-mediated platelet destruction.

Adult↗
PubMed1987

Platelet intermediate filaments: detection of a vimentinlike protein in human and bovine platelets.

Human and bovine platelets contain a 58,000-dalton vimentinlike protein that cross-reacts with antivimentin antibody. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blots indicate that this protein is present in whole platelet lysates and triton insoluble cytoskeletons. Transmission electron microscopy of platelets reveals an isotropic network of individual intermediate filaments distributed throughout the platelets. High salt, triton extracted, glutaraldehyde and tannic acid fixed platelets reveal 10-nm filaments that can be seen to form a peripheral ring, as well as an isotropic network in the body of the cells. Indirect immunofluorescence of resting and spread platelets demonstrates a circumferential staining pattern close to the cell membrane, with additional fibrillar staining throughout the platelets. Our data suggest that the 58,000-dalton vimentinlike protein may be associated with the microtubule coil and the plasma membrane, and may thus help to maintain the resting platelet's discoid shape.

Animals↗
PubMed1988

Inhibition of neutrophil functions by platelets and platelet-derived products: description of multiple inhibitory properties.

The effect of platelets and their products on in vitro responses of human neutrophils to f-met-leu-phe (fMLP) and phorbol myristate acetate (PMA) was studied. Platelets produced a concentration-dependent inhibition of neutrophil superoxide anion (O2-) generation with maximum inhibition of the response to fMLP approaching 42.2 +/- 5.4% and that to PMA approaching 85.9 +/- 3.4%. Supernates of thrombin-activated platelets produced maximal inhibition of neutrophil O2- generation in response to fMLP (66.3 +/- 4.2%) at a ratio of 10 platelet equivalents (PEQ) to 1 neutrophil but failed to affect the cells' response to PMA. In contrast, lysate of sonicated platelets inhibited neutrophil O2- generation in response to both fMLP (59.6 +/- 2.0%) and PMA (90.1 +/- 1.3%). Biochemical characterization of platelet lysate identified at least two stimulus-specific inhibitory activities which differ in size, thermal stability and enzyme sensitivity. Platelet lysate also maximally inhibited neutrophil degranulation and chemotaxis at a ratio of 20 PEQ to 1 neutrophil. Our findings indicate that physiologically achievable levels of platelets or their products modulate the response of neutrophils in a stimulus-specific manner and are thereby capable of potentially limiting tissue damage which accompanies neutrophil activation during inflammation.

Anti-Inflammatory Agents↗
PubMed1978

Metabolism of arachidonic acid by platelets: utilization of arachidonic acid by human platelets in presence of linoleic and dihomo-gamma-linolenic acids.

In vitro human platelet prostaglandin synthesis has been studied from added radioactive arachidonic acid (i) as function of substrate concentration, (ii) as function of platelet concentration and (iii) as function of pH. Platelets, as in platelet rich plasma when labelled with arachidonic acid, washed and treated with thrombin, released radioactivity mainly from phosphatidylcholine and phosphatidylinositol. The released radioactivity was mostly accounted for by the formation of the previously identified oxygenation products of arachidonic acid. Platelet utilization or arachidonic acid was also studied in presence of linoleic and dihomo-gamma-linolenic acids, the two essential fatty acids known for antithrombotic effect. At its high concentrations linoleic acid decreased platelet cyclo-oxygenase activity as seen by a decreased formation of endoperoxides from arachidonic acid. Dihomo-gamma-linolenic acid was found to be a mutually competitive substrate with arachidonic acid for the platelet prostaglandin synthetase thus causing reduced utilization of arachidonic acid as shown by measuring the various oxygenation products of arachidonic acid. These two acids were utilized differently by platelet prostaglandin synthetase.

8,11,14-Eicosatrienoic Acid↗
PubMed2002

Forced swimming test and fluoxetine treatment: in vivo evidence that peripheral 5-HT in rat platelet-rich plasma mirrors cerebral extracellular 5-HT levels, whilst 5-HT in isolated platelets mirrors neuronal 5-HT changes.

Low levels of central serotonin (5-HT) have been related to the state of depression, and 5-HT is the major target of the newer antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs). Neurons and platelets display structural and functional similarities, so that the latter have been proposed as a peripheral model of central functions. In particular, in blood more than 99% of 5-HT is contained in platelets, so that one could consider changes in 5-HT levels in platelets as a mirror of changes in central 5-HT. Here, this hypothesis has been studied via the analysis of the influence of: (1) the forced swimming test (FST, which has been proved to be of utility to predict the clinical efficacy of antidepressants in rodents) and (2) treatment with the SSRI fluoxetine upon 5-HT levels monitored in brain regions and in peripheral platelets by means of electrochemical in vivo and ex vivo measurements. The results obtained confirm that the FST increases immobility; furthermore they show a parallel and significant decrease in cerebral (brain homogenate) and peripheral (in platelet-rich plasma, PRP) voltammetric 5-HT levels following the FST in naive rats. In addition, subchronic treatment with fluoxetine was followed by a significant increase in 5-HT levels in PRP, while the same SSRI treatment performed within the FST resulted in a decrease in the 5-HT levels in PRP. However, this decrease was inferior to that observed without SSRI treatment. These data suggest that there is an inverse relationship between immobility and the levels of 5-HT in PRP and that these peripheral 5-HT levels are sensitive to: (1) the FST, (2) the treatment with fluoxetine and (3) the combination of both treatments, i.e. SSRI + FST. It has been reported that SSRI treatment at first inhibits the 5-HT transporter in brain, resulting in increased extracellular 5-HT, while following sustained SSRI treatments decreased intracellular levels of central 5-HT were observed. Accordingly, the present data show that the initial block of 5-HT reuptake is revealed by the selective increase in 5-HT levels (extracellular content) measured in PRP (not in insulated platelets, IPs) the 1st day of fluoxetine treatment. The initial action of this SSRI upon the 5-HT transporter in brain has also been confirmed by in vivo voltammetric data showing selective increase in the serotonergic signal following local injection of fluoxetine into the brain region studied. Successively, the major effect monitored is a decrease in 5-HT levels, which is more evident in IPs than in PRP. However, it is known that following 2 weeks treatment with an SSRI, 5-HT autoreceptors are desensitized and the serotonin synthesis is restored, together with the intracellular 5-HT levels. The present data showing that the levels of 5-HT in IPs tend to return to control values 12 days after the beginning of chronic fluoxetine treatment suggest that 5-HT levels in IPs (intracellular environment) mirror the influence of SSRI treatment upon the central 5-HT system. On the other hand, at day 12 of the chronic fluoxetine treatment, 5-HT content remains low in PRP. Similarly, low levels of 5-HT have been monitored in brain homogenate of rats chronically treated with fluoxetine. This would support the similarity between PRP preparation and brain homogenate as in both cases cells are disrupted by sample preparation. In conclusion this work supports the literature in proposing platelets as a peripheral model of central functions. In particular, the present data support the idea that peripheral 5-HT platelet levels can reflect the state of the central 5-HT system in conditions of depression. Furthermore, the main outcome of this study is that PRP may mirror central extracellular 5-HT levels, whilst IPs mirror neuronal 5-HT changes.

Animals↗