Fatma Tore

Passage of VIP / PACAP / Secretin Family Across the Blood-Brain Barrier: Therapeutic Effects

In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimers disease, amyotropic lateral sclerosis, Parkinsons disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.

Vasoactive intestinal peptide inhibits degranulation and changes granular content of mast cells: a potential therapeutic strategy in controlling septic shock

Vasoactive intestinal peptide (VIP) has potent protective activity against sepsis and increases the survival rate of septic rats and mice. The present study was planned to evaluate the effect of VIP on mast cell activity, histamine and methylhistamine levels and oxidative stress in the liver and kidneys of septic rats. The effect of VIP was compared to that of nitric oxide synthesis inhibition, previously tested extensively in septic shock models, with doubtful benefit. The present study showed that endotoxic shock did not lead to oxidative stress in either liver or kidney of the rats. On the other hand, mast cells, based on their location, displayed functional heterogeneity to the septic insults. VIP possibly modulated the specific reactions of the tissues to mediators released from mast cells during septic shock. The most prominent effect of VIP as compared to nitric oxide synthesis inhibition was related to mast cells. In conclusion, the prevention of mast cell reactivity by VIP could be a potential therapeutic strategy in controlling septic shock.

Sympathetic skin responses of the face and neck evoked by electrical stimulation

The sympathetic skin responses (SSRs) were recorded from different facial regions and neck in 25 subjects evoked by electrical stimulation of the median nerve at the wrist. Recordings from all regions were cross-compared with each other and within right and left sides individually. In one subject postauricular SSR, and in another subject upper lip SSR could not be elicited on both sides. Other responses could be obtained in all the remaining subjects. In 11 subjects, the responses did not appear by the first stimulus, and began to appear by repeated stimuli. Mean latencies and the highest amplitudes of the responses were similar for both sides. Gradual amplitude increase was observed in the first three or four set of responses in 20 subjects, although the stimulus intensity was constant. In conclusion, face and neck SSRs are symmetric, can be evoked by electrical stimulation and can be used to investigate the sympathetic innervation of these areas.

Vasoactive Intestinal peptide modulates c-Fos activity in the trigeminal nucleus and dura mater mast cells in sympathectomized rats.

Neurogenic inflammation in the dura mater caused by trigeminal nociceptive activation has been implicated in the pathophysiology of migraine. Vasoactive intestinal polypeptide (VIP) is a powerful neuroprotective neuropeptide that can modulate mast cell behavior. Migraine is also associated with sympathetic insufficiency. This study investigates the effects of VIP on the number of mast cells in the dura mater and on c‐Fos expression in the trigeminal nucleus of sympathectomized rats. Experiments were carried out with 32 Sprague‐Dawley male rats with body weights of 200–250 g. In the sympathectomized group, the left superior cervical sympathetic ganglion was removed. In the sympathectomized + VIP group, postoperative VIP 25 ng/kg/day (0.2 ml) was administered for 5 days. In the sham group, the ganglion and nerves were exposed but not dissected. Dura maters were stained with toluidine blue, and brainstems were labeled by indirect immunohistochemistry for c‐Fos. Sympathectomy significantly increased the number of mast cells in both the ipsilateral and the contralateral dura mater (P < 0.001). VIP decreased the number of mast cells in both sides of the dura mater in sympathectomized rats. VIP also decreased c‐Fos expression in the ipsilateral trigeminal nucleus of sympathectomized rats (P < 0.001). In the context of an experimental superior cervical ganglionectomy model of migraine, VIP is an efficient modulator of neurogenic inflammation of the dura.

Salmon calcitonin ameliorates migraine pain through modulation of CGRP release and dural mast cell degranulation in rats

The exact mechanism of migraine pathophysiology still remains unclear due to the complex nature of migraine pain. Salmon calcitonin (SC) exhibits antinociceptive effects in the treatment of various pain conditions. In this study, we explored the mechanisms underlying the analgesic effect of salmon calcitonin on migrane pain using glyceryltrinitrate (GTN)‐induced model of migraine and ex vivo meningeal preparations in rats. Rats were intraperitoneally administered saline, GTN (10 mg/kg), vehicle, saline + GTN, SC (50 μg/kg) + GTN, and SC alone. Also, ex vivo meningeal preparations were applied topically 100 μmol/L GTN, 50 μmol/L SC, and SC + GTN. Calcitonin gene‐related peptide (CGRP) contents of plasma, trigeminal neurons and superfusates were measured using enzyme‐immunoassays. Dural mast cells were stained with toluidine blue. c‐fos neuronal activity in trigeminal nucleus caudalis (TNC) sections were determined by immunohistochemical staining. The results showed that GTN triggered the increase in CGRP levels in plasma, trigeminal ganglion neurons and ex vivo meningeal preparations. Likewise, GTN‐induced c‐fos expression in TNC. In in vivo experiments, GTN caused dural mast cell degranulation, but similar effects were not seen in ex vivo experiments. Salmon calcitonin administration ameliorated GTN‐induced migraine pain by reversing the increases induced by GTN. Our findings suggested that salmon calcitonin could alleviate the migraine‐like pain by modulating CGRP release at different levels including the generation and conduction sites of migraine pain and mast cell behaviour in the dura mater. Therefore salmon calcitonin may be a new therapeutic choice in migraine pain relief.

The effect of kisspeptin on spermatogenesis and apoptosis in rats

BACKGROUND/AIM To study the effect of kisspeptin, a gonadotropin release stimulator, on the testicular tissue of the rat. MATERIALS AND METHODS Four groups were formed as follows: control, Kiss-10 501397645907nmol administration for 1 day, Kiss-10 administration for 13 days, and one last group kept for 7 days following Kiss-10 applied for 13 days. Testicular tissues were stained with hematoxylin-eosin, periodic acid Schiff, Masson trichrome staining, terminal deoxynucleotidyl transferased UTP nick-end labeling, and Ki-67 immune staining. Serum testosterone levels were determined. RESULTS Serum testosterone level increased following acute application, while it was reduced by chronic treatment. Spermatogenic cells as stained by Ki-67 and TUNEL increased in the treated groups compared to the controls. Following a 7-day rest after treatment, a decrease in testosterone levels and Ki-67-stained cell numbers and an increase in TUNEL-stained cells were observed. Leydig cells showed increased vacuolization in the Kiss-1 group. Leydig cell vacuolization continued in the Kiss (13) group and was reduced in the Kiss (13 + 7) group. CONCLUSION Kiss-10 increased spermatogenic cell proliferation, while testosterone level and proliferation decreased and apoptosis increased during the waiting period.

Trimetazidine increases cell survival and inhibits the activation of inflammatory response in sodium taurocholate-induced acute pancreatitis

Objective: To evaluate the therapeutic effects of trimetazidine (TMZ) in an experimental acute pancreatitis (AP) model induced with sodium taurocholate (STC). Summary of Background Data: At present...

Mast Cell Degranulation Mediates Compound 48/80-İnduced Meningeal Vasodilatation Underlying Migraine Pain

Objective: The cranial dura mater contains plenty of mast cells and is principally supplied by the middle meningeal artery which has a key role in the generation of headaches. Neurogenic inflammation caused by perivascular nerve activation and dural vasodilation is held responsible for migraine pain. Dural mast cells contribute neurogenic inflammation and migraine via vasoactive and proinflammatory mediators in their secretory granules. In the present study, it was aimed to investigate vasoactive effect of mast cell degranulating agent compound 48/80 induced dural mast cell degranulation on the middle meningeal artery and its anterior and posterior branches. Methods: Isolated skulls obtained from male Wistar rats were divided into 2 halves. The skull cavities with intact the dura mater were applied synthetic interstitial fluid for control group or mast cell degranulating agent compound 48/80 (10 μg/ml) in synthetic interstitial fluid for treated group at 37 o C for 15 min. Diameters of middle meningeal artery and its anterior and posterior branches were measured and mast cells were counted from whole-mount preparations of meningeal dura mater. Results: While compound 48/80 induced massive degranulation of dural mast cells (P<0.01), it did not change the number of mast cells in the dura mater. Moreover, compound 48/80 increased diameter of middle meningeal artery (P<0.01) and its anterior (P<0.05) and posterior (P<0.01) branches, respectively compared to synthetic interstitial fluid treatment. Conclusion: Dural mast cell degranulation causes dilatation of middle meningeal artery which is involved in the pathophysiology of migraine, therefore testing of mast cell stabilizing agents in vivo models of migraine pain may promise hope for the next big things in the treatment of migraine headaches.