The current status of reversal therapy in Japan for elderly patients with head injury treated with antithrombotic agents: A prospective multicenter observational study.

Background: Acute exacerbation of head injury in elderly patients due to use of antithrombotic agents has become a concern in countries with aging populations. Reversal agents are recommended for treatment, but its usage is unclear. Therefore, we conducted a prospective observational study in this patient population to monitor usage of reversal therapy. Methods: The subjects were 721 elderly patients aged ≥65 years old who were hospitalized in 15 centers from December 2019 to May 2021. Patients were divided into groups who did not receive antithrombotic agents (Group A), who received antithrombotic agents, but did not receive reversal therapy (Group B), and were treated with antithrombotic agents and reversal therapy (Group C). Age, gender, mechanism of injury, neurologic and imaging findings on admission, clinical course after admission and surgery, outcomes and complications were compared among these groups. Time from injury to reversal therapy was examined based on outcomes to investigate trends in the timing of administration of the reversal agent. Results: Acute exacerbation during the clinical course occurred in 9.8 %, 15.8 % and 31.0 % of cases in Groups A, B and C, respectively, and differed significantly among the groups. On head CT, the incidences of hematoma were 35.7 %, 36.5 % and 60.4 %, respectively, with this incidence being significantly higher in Group C; and the respective rates of craniotomy were 18.8 %, 14.0 % and 50.9 %, again with this rate being significantly higher in Group C. The good outcome and mortality rates were 57.1 %, 52.5 % and 35.8 %, and 14.5 %, 18.0 % and 24.5 %, respectively, and both were poorest in Group C. Times from injury to treatment with a reversal agent were significantly shorter in patients without compared to those with acute exacerbation (405.9 vs. 880.8 min) and in patients with favorable outcomes compared to those with unfavorable outcomes (261.9 vs. 543.4 min). Conclusion: Similarly to previous studies, the incidence of acute exacerbation was increased by use of antithrombotic agents. These results suggest that patients in Japan who require hematoma evacuation due to symptom exacerbation tend to be treated with reversal agents. Although it is difficult to assess the efficacy of reversal therapy from this study, earlier treatment with reversal agents before the occurrence of acute exacerbation may be useful to improve outcomes.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity: Prespecified Subgroup Analysis of the ANNEXA-4 Study in Japan.

AIMS: Andexanet alfa, a specific antidote to factor Xa (FXa) inhibitors, has been approved for clinical use in several countries, including Japan, based on the results from the phase 3 trial ANNEXA-4. We aimed to assess the efficacy and safety of andexanet alfa treatment in FXa inhibitor-related acute major bleeding in patients enrolled for ANNEXA-4 in Japan. METHODS: This prespecified analysis included patients enrolled at Japanese sites in the prospective, open-label, single-arm ANNEXA-4 trial. Eligible patients had major bleeding within 18 hours of oral FXa inhibitor administration. The coprimary efficacy endpoints were percent change in anti-FXa activity and proportion of patients achieving excellent or good hemostatic efficacy 12 hours post-treatment. RESULTS: A total of 19 patients were enrolled, all of whom had intracranial hemorrhage; 16 patients were evaluable for efficacy. Median percent reduction in anti-FXa activity from baseline to nadir was 95.4% in patients taking apixaban, 96.1% in patients taking rivaroxaban, and 82.2% in patients taking edoxaban. Overall, 14/16 patients (88%) achieved excellent or good hemostasis (apixaban, 5/5; rivaroxaban, 6/7; edoxaban, 3/4). Within 30 days, treatment-related adverse events (AEs) and serious AEs occurred in 2 and 5 patients, respectively. One patient died during follow-up, and 2 patients experienced thrombotic events. CONCLUSION: Treatment with andexanet alfa rapidly reduced anti-FXa activity with favorable hemostatic efficacy in Japanese patients with acute major bleeding. Serious AEs of thrombotic events during rapid reversal of anti-FXa activity arose as particular safety concerns in this population as with previous studies.

Olfactory hallucinations caused by an unruptured posterior communicating artery aneurysm improved by clipping: A case report with literature review.

Background: Unruptured cerebral aneurysms that lead to epilepsy are rare and olfactory hallucinations caused by such an aneurysm are extremely rare. Various treatments have been proposed, including wrapping, clipping with or without cortical resection, and coil embolization, but there is no consensus on the best approach. Case Description: We present a case of a 69-year-old female who experienced olfactory hallucinations caused by a posterior communicating artery aneurysm and was treated with clipping without cortical resection, with a positive outcome. Conclusion: According to our knowledge, there has been only one report of a posterior communicating artery aneurysm presenting with olfactory hallucinations has been reported, where clipping and cortical resection were performed. This is the first report of a posterior communicating artery aneurysm with olfactory hallucinations that was effectively treated with clipping alone. There have been a few similar reports of large middle cerebral artery aneurysms, most of which are believed to be caused by entorhinal cortex compression. Although a definitive treatment protocol for this condition remains elusive, we suggest that elimination of the pulsatile compressive stress exerted on the cerebral cortex through surgical clipping or coil embolization is crucial for achieving efficacious seizure management.

Current Therapeutic Drugs Against Cerebral Vasospasm after Subarachnoid Hemorrhage: A Comprehensive Review of Basic and Clinical Studies.

BACKGROUND: Cerebral vasospasm (CVS) is well known as a major complication in subarachnoid hemorrhage (SAH) patients, and research has long been focused on improving morbidity and mortality. As CVS commonly develops from day 4 to day 14 after SAH onset, SAH patients require therapies with drugs for preventing CVS after surgical treatment for the source of hemorrhage, mostly ruptured intracranial aneurysms. It is thought that the pathogenesis of CVS is initiated by prolonged smooth muscle contraction, and the subsequent hypoperfusion and cytotoxic responses induce cerebral ischemia. Although therapeutic investigations have historically focused on morphological improvement, the improvement of outcome is limited by the reversal of arterial narrowing. Therefore, it might be important to look back at evidence from long-lasting studies of CVS and to determine a highroad to effective drugs, including combination therapy. OBJECTIVE: In this review, we introduce current candidate beneficial drugs against CVS in clinical SAH, including nimodipine and other Ca2+ channel antagonists, magnesium sulfate, clazosentan, statins, cilostazol, eicosapentaenoic acid, fasudil hydrochloride, milrinone, and edaravone, all of which have been frequently studied in recent years.

Bilateral posterior fossa chronic subdural hematoma treated with craniectomy: Case report and review of the literature.

BACKGROUND: Posterior chronic subdural hematomas (pCSHs) are rare. Their diagnosis and treatment are difficult. DESCRIPTION: A 69-year-old woman was admitted to our hospital with nausea, headache, and mild consciousness disturbance. Computed tomography and magnetic resonance imaging showed bilateral pCSH. To prevent further neurological deterioration, we performed surgery under general anesthesia by midline suboccipital craniectomy. Unexpected bleeding from a developed circuitous occipital sinus was stopped with hemoclips. After hematoma removal, she recovered and was transferred to a rehabilitation hospital. By the 19(th) postoperative day, she had developed no neurologic deficits. CONCLUSION: This experience demonstrates the risk of blind surgical therapy in patients with pCSH. In such patients, posterior fossa craniectomy may be preferable in terms of diagnosis and safe treatment.

A spontaneous superficial temporal artery pseudoaneurysm possibly related to atherosclerosis: Case report and review of literature.

BACKGROUND: Spontaneous superficial temporal artery (STA) pseudoaneurysms are very rare; only four cases, including ours, have been reported to date. Therefore, the cause of them has not been studied. CASE DESCRIPTION: A 57-year-old woman was admitted to our hospital with a pulsatile mass in the left preauricular region. Her medical history included hypertension, dyslipidemia, and angina pectoris. She denied a history of head injury or minor head trauma. Three-dimensional computed tomography angiography showed a well-enhanced saccular aneurysm on the main trunk of the STA. To prevent rupture it was removed surgically. The histological diagnosis was pseudoaneurysm with atherosclerosis. By the 2(nd) postoperative day, she had completely recovered and was discharged home. There has been no relapse. CONCLUSIONS: As all four documented patients were at high risk for atherosclerosis, we posit that a causal factor was weakening of the arterial wall due to atherosclerosis and chronic pressure on the STA from anatomical structures. Here, we present histological evidence to support this hypothesis.

5-HT2A receptor antagonist M100907 reduces serotonin synthesis: an autoradiographic study.

The effects of the administration of the serotonin (5-HT)(2A) antagonist, M100907, on 5-HT synthesis rates, were evaluated using the α-[(14)C]methyl-l-tryptophan (α-MTrp) autoradiographic method. In the treatment study, M100907 (10mg/kg) was injected intraperitoneally 30 min before the α-MTrp injection (30 µCi over 2 min). A single dose of M100907 caused a significant decrease in the synthesis in the anterior olfactory nucleus, accumbens nucleus, frontal cortex, sensory-motor cortex, cingulate cortex, medial caudate-putamen, dorsal thalamus, substantia nigra, inferior collicus, raphe magnus nucleus, superior olive, and raphe pallidus nucleus. These data suggest that the terminal 5-HT(2A) receptors are involved in the regulation of 5-HT synthesis in the entire brain. Further, 5-HT synthesis is likely regulated by the 5-HT(2A) antagonistic property of M100907 in the cortices, anterior olfactory nucleus, caudate putamen, and nucleus accumbens.

Chronic citalopram treatment elevates serotonin synthesis in flinders sensitive and flinders resistant lines of rats, with no significant effect on Sprague-Dawley rats.

The influence of citalopram on regional 5-hydroxytryptamine (serotonin, 5-HT) synthesis, one of the most important presynaptic parameters of serotonergic neurotransmission, was studied. Sprague-Dawley (SPD) rats were used as the controls, and Flinders Resistant Line (FRL) rats were used as auxiliary controls, to hopefully obtain a better understanding of the effects of citalopramon Flinders Sensitive Line (FSL; "depressed") rats. Regional 5-HT synthesis was evaluated using a radiographic method with a labelled tryptophan analog tracer. In each strain of rats, the animals were treated with citalopram (10 mg/(kg day)) or saline for 14 days. The groups consisted of between fourteen and twenty rats. There were six groups of rats with citalopram (CIT) and saline (SAL) groups in each of the strains (SPD-AL, SPD-IT, FRL-AL, FRL-IT, FSL-AL and FSL-IT). A two-factor analysis of variance was used to evaluate the effect of the treatment c., SPD-SAL relative to SPD-CIT) followed by planned comparisons to evaluate the effect in each brain region. In addition, the planned comparison with appropriate contrast was used to evaluate a relative effects in SPD relative to FSL and FRL, and FSL relative to FRL groups. A statistical analysis was first performed in the a priori selected regions, because we had learned, from previous work, that it was possible to select the brain regions in which neurochemical variables had been altered by the disorder and subsequent antidepressant treatments. The results clearly show that citalopram treatment does not have an overall effect on synthesis in the control SPD rats; there was no significant (p > 0.05) difference between the SPD-SAL and SPD-CIT rats. In "depressed" FSL rats, citalopram produced a significant (p < 0.05) elevation of synthesis in seventeen out of thirty-four regions, with a significant (p < 0.05) reduction in the dorsal and median raphe. In the FRL rats, there was a significant (p < 0.05) elevation in the synthesis in twenty-two out of thirty-four brain regions, with a reduction in the dorsal raphe. In addition to these regions magnus raphe was different in the SPD and FSL groups, but it was on the statistical grounds identified as an outlier. There were significant changes produced in the FSL and FRL rats in thirteen out of seventeen a priori selected brain regions, while in the SPD rats, citalopram produced significant changes in only four out of seventeen a priori selected regions. The statistical evaluation also revealed that changes produced by citalopram in the FSL and FRL rats were significantly greater than those in the SPD rats and that there was no significant difference between the effect produced in the FSL and FRL rats. The presented results suggest that in "depressed" FSL rats, the antidepressant citalopram elevates 5-HT synthesis, which probably in part relates to the reported improved in behaviour with citalopram.

Both acute and chronic buspirone treatments have different effects on regional 5-HT synthesis in Flinders Sensitive Line rats (a rat model of depression) than in control rats.

The main objective of this investigation was to evaluate the effects of buspirone, a 5-HT(1A) agonist with some partial agonist properties and also an antidepressant, on regional 5-HT synthesis in Flinders Sensitive Line (FSL) rats ("depressed"), and to compare the effects to the Flinders Resistant Line (FRL) control rats (not "depressed"). In addition results were compared to those previously reported in normal Sprague-Dawley (SPD) rats (normal control). Serotonin synthesis in both FSL and FRL rats was measured following acute and chronic treatments with buspirone. Both of these strains were derived from the SPD rats. No direct comparison was done between the FSL saline and FRL saline groups, or the FSL buspirone and FRL buspirone groups, because the objective of the studies was to evaluate effects of buspirone in these two strains. The results show that acute treatment with buspirone elevates 5-HT synthesis throughout the brain in the FRL rats. In the FSL rats, there were reductions in some brain regions (e.g., dorsal and median raphe, amygdala, anterior olfactory nucleus, substantia nigra reticulate), while in other regions, there were increases in the synthesis observed (e.g., frontal, parietal, visual and somatosensory cortices, ventral hippocampus). In 20 out of the 30 brain regions investigated in the FSL rats, there was no significant change in the synthesis following acute buspirone treatment. During the chronic treatment, buspirone produced a significant reduction of 5-HT synthesis in 15 out of 30 brain regions in the FRL rats. In the FSL rats, buspirone produced a significant elevation of the synthesis in 10 out of 30 brain regions. In both the FSL and FRL rats, buspirone produced rather different effects than those reported previously for SPD (normal) rats. The acute effect in the FSL rats was somewhat similar to the effect reported previously for the SPD rats, while in the FRL rats, the acute buspirone treatment produced an effect observed previously in treatments with 5-HT(1A) antagonists suggesting an action of buspirone as partial agonist in FRL rats. The data suggest that with respect to 5-HT synthesis, FRL rats differ from SPD rats (a natural control; normal rats) and, as such, indicate that when the effects related to the serotonergic system (e.g., influence of serotonergic drugs) are studied in the FSL rats and compared to those in the FRL rats, any conclusions drawn may not reflect differences relative to a normal rat.

Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats.

The olfactory bulbectomized (OBX) rat is considered to be a good model of the pathology of human depression and also of the functional actions of antidepressant drug therapy. It has been proposed that antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) can be accelerated by blocking 5-HT(1A/B) autoreceptors with pindolol. The underlying mechanism is thought to involve acute unrestricting of 5-HT release and, consequently, relatively enhanced 5-HT turnover throughout the forebrain serotonergic networks. The effect of this combination on 5-HT turnover in sham operated or OBX rats can be assessed at the level of 5-HT synthesis, a very important presynaptic step in serotonergic neurotransmission, using the alpha-[(14)C]methyl-l-tryptophan autoradiography method. In sham rats, acute citalopram (20mg/kg) treatment increased synthesis at almost all serotonergic terminal regions but slightly decreased synthesis at serotonergic cell body regions (i.e. dorsal and median (not significant) raphe; approximately 16%). Combining pindolol (10mg/kg) with citalopram further increased synthesis at many regions in sham rats (relative to treatment with only citalopram). In OBX rats, citalopram decreased synthesis at a few terminal regions and greatly decreased synthesis at the dorsal and median raphe ( approximately 45%; relative to OBX rats treated with saline). Combining pindolol with citalopram greatly increased synthesis at almost all regions in OBX rats (relative to treatment with only citalopram). These results suggest that acute citalopram effects result in elevated terminal 5-HT synthesis, but these effects are restrained by 5-HT(1A/B) autoreceptor feedback to different degrees in sham and OBX rats. Moreover, 5-HT(1A/B) autoreceptor feedback is stronger in OBX rats and may underlie the delay of SSRI effects in OBX rats and, correspondingly, in human depression. Pindolol acceleration and augmentation of SSRI antidepressant therapy for human depression may be mediated by attenuation of 5-HT(1A/B) autoreceptor feedback, permitting unhindered SSRI effects on serotonergic terminals.

Acute citalopram has different effects on regional 5-HT synthesis in FSL, FRL, and SDP rats: an autoradiographic evaluation.

In this study, we measured the effect of an acute treatment of citalopram on 5-hydroxytryptamine (5-HT) synthesis in a genetic rat model of depression, the Flinders Sensitive Line (FSL) rats, their counterparts, the Flinders Resistant Line (FRL) rats, and outbred Sprague-Dawley (SPD) rats, using the alpha-[(14)C]methyl-l-tryptophan (alpha-MTrp) autoradiographic method. A comparison of 5-HT synthesis in the FSL rats treated with citalopram (FSL-CTP) and those treated with saline (FSL-SAL) indicate that citalopram reduces global 5-HT synthesis in the FSL rats, as well as in all the brain areas investigated. The reduced synthesis was also observed in the dorsal raphe (DR) nucleus and the median raphe (MR) nucleus. The comparison of the synthesis between the citalopram-treated SPD rats (SPD-CTP) and the saline-treated SPD rats (SPD-SAL) revealed a global increase of 5-HT synthesis in the SPD-CTP group, as well as an increase in some terminal areas, but a reduction in the DR and the MR. In contrast to the reduction throughout the brain in the FSL rats, the FRL rats treated with citalopram (FRL-CTP), when compared to the saline group (FRL-SAL), showed a global increase of 5-HT synthesis, as well as in most of the terminal areas and in the DR and the MR. The reduction of 5-HT synthesis throughout the brain in the FSL rats is likely, in part, a result of reported supersensitivity of the 5-HT(1A) receptors. Comparing changes in the SPD, FRL, and FSL rats treated with citalopram to their respective controls (saline-treated rats), the FSL rats treated acutely with citalopram were the only rats that exhibited lower 5-HT synthesis rates in all of the limbic areas, the basal ganglia, and the neocortices. This may be related to the pathophysiological basis of depressive characteristics in FSL rats. The citalopram treatment produced unexpected results in the FRL rats: 5-HT synthesis was elevated not only in most of the terminal areas, but also in the cell body areas, the DR and MR. The increase of 5-HT synthesis throughout the brain in the FRL rats is likely, in part, a result of the reported subsensitivity of the 5-HT(1A) receptors, and possibly other sites through which 5-HT synthesis could be controlled (e.g., 5-HT(1B)). In addition differences in intracellular signaling could be at least in part responsible for these differences.

Usefulness of balloon test occlusion in the diagnosis of glossopharyngeal neuralgia. Case report.

A 67-year-old man presented with glossopharyngeal neuralgia (GPN) manifesting as severe paroxysmal pharyngeal and retroauricular pain not controlled by medical treatment. Constructive interference in steady state magnetic resonance imaging suggested that the responsible vessel was the right vertebral artery (VA). As carbamazepine had some limited effect, we reviewed the appropriateness of microvascular decompression surgery. Balloon test occlusion of the VA was performed to confirm that the GPN was due to right VA pulsation. The neuralgia disappeared and reappeared with balloon inflation and deflation. Therefore, the VA was moved to decompress the glossopharyngeal nerve. The patient was pain-free after surgery. Balloon test occlusion may be useful in the diagnosis of GPN and the selection of the most appropriate surgical treatment.

Rapidly enlarging chordoid meningioma with abundant mucin production.

This 77-year-old woman with a rapidly enlarging chordoid meningioma first noticed a growing, non-pulsatile, nonpainful soft mass in the left temporal region after a head trauma 2 years earlier. Neuroimaging showed a homogeneously enhanced osteolytic mass lesion in the left temporal bone. Surgery revealed an extradural tumor without significant adhesions. Histopathologically it was a meningioma with features reminiscent of chordoma. Most of the tumor cells contained mucin-rich chordoid elements. Immunohistochemically, the lesion was positive for vimentin and epithelial membranous antigen; it was negative for cytokeratin and S-100 protein. Based on these findings a diagnosis of chordoid meningioma was made. We posit that the rapid enlargement of the tumor over a relatively short period was attributable to its high mucin-producing activity.

Acute effects of moclobemide and deprenyl on 5-HT synthesis rates in the rat brain: An autoradiographic study.

Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) released from nerve terminals in the brain are primarily removed from the synaptic cleft by a reuptake mechanism. In part, the homeostasis is maintained by monoamine oxidase (MAO) deamination achieved primarily intracellularly. The present study's aim was to examine the effect of the acute administration of the MAO inhibitors, moclobemide (a MAO-A inhibitor) and deprenyl (a MAO-B inhibitor), on 5-HT synthesis rates, measured in discrete regions of the rat brain by an autoradiographic method, using alpha-[14C]methyl-l-tryptophan as a tracer. MAO inhibitors have different effects on 5-HT synthesis rates in the cell bodies and areas of the nerve terminals. Moclobemide (10 mg/kg, i.p. 30 min before the tracer injection) and deprenyl (3 mg/kg, i.p. 2 h before the tracer injection) decreased the 5-HT synthesis rates in the dorsal (-18% and -22%) and median (-22% and -33%) raphe, respectively. Moclobemide also significantly decreased 5-HT synthesis in the entire nerve terminal areas investigated. The reductions were between 23% (cingulate cortex) and 50% (locus coeruleus). Deprenyl did not significantly affect 5-HT synthesis in the nerve terminals. The present results suggest that MAO-A, and to a lesser extent, MAO-B, are involved in the regulation of 5-HT synthesis in the rat brain. The mechanism(s) of MAO inhibitors' action on 5-HT synthesis in the raphe nuclei are probably related to an increase in the extraneuronal 5-HT concentration and also to the interaction between the serotonergic and catecholaminergic neurons. The reduction of 5-HT synthesis in the raphe nuclei likely occurs by an action of extracellular 5-HT via the dendritic autoreceptors with a possible contribution from the action of extracellular DA and NE. In the terminal regions, the most likely mechanism is via the presynaptic autoreceptors through which elevated extraneuronal 5-HT acts on synthesis control. However, there is also a possibility that the elevation in intraneuronal 5-HT directly inhibits its synthesis, especially following deprenyl treatment. A great influence of moclobemide on 5-HT synthesis could be related to its antidepressant action.

Histological study of paramedian dorsal root ganglia in an infant with split cord malformation. Case report.

The authors present a histological study of resected tissue obtained from an 18-month-old girl with split cord malformation Type II whose right foot was smaller than her left. Magnetic resonance imaging revealed duplication of the spinal cord below the level of L-1. On laminectomy it was discovered that the cord was tethered in the lumbosacral region. The resected tissue contained the cluster of paramedian dorsal root ganglia unique to this congenital anomaly. On histological examination, the ganglion cells expressed not only neuronal markers but also a marker for muscle cells indicative of pathological development of the midline structure. Further histological study is necessary to gain a deeper insight into this congenital disease and to obtain additional information for use in surgical planning.

Chronic buspirone treatment normalizes regional serotonin synthesis in the olfactory bulbectomized rat brain: an autoradiographic study.

The effects of chronic buspirone treatments, administered by minipump at doses of 10 and 20 mg/(kg day) for 14 days, on brain 5-HT synthesis in olfactory bulbectomized (OBX) rats were evaluated. The alpha-[14C]methyl-L-tryptophan autoradiographic method was used. We compared the synthesis in the buspirone treated OBX rats (administered either 10 mg/(kg day) (OBX-10) or 20 mg/(kg day) (OBX-20)) to that of the saline treated OBX rats (OBX-SAL), and the sham operated rats (SHX) treated with saline. In addition, OBX-10 rats were compared to SHX rats treated with 10 mg/(kg day) (SHX-10) of buspirone. All treatments were carried out for 14 days. Adult Sprague-Dawley rats were used. Two weeks following the OBX or SHX procedures, the rats were assigned to the OBX-10, OBX-20, OBX-SAL, SHX-10, or SHX-SAL groups, respectively. The 5-HT synthesis rates R (pmol/(g/min)) were calculated from the trapping constant of alpha-[14C]MTrp (K*; ml/(g min)) and the plasma concentration of the plasma non-protein-bound tryptophan (Cp; pmol/ml) using the lumped constant (LC) measured previously in the rat brain. There was no significant difference in the plasma free or total tryptophan among these groups. The overall synthesis in the OBX-10 group was not statistically different from the OBX-SAL group, but it was different from the OBX-20 and SHX-SAL groups. The OBX-20 rats had an overall significant reduction in 5-HT synthesis, when compared to the OBX-SAL group, but did not differ from the SHX-SAL group, which did not differ from the SHX-10 group. These results suggest that 10 mg/(kg day) of buspirone for 14 days in the OBX rats did not produce a significant alteration in 5-HT synthesis, but 20 mg/(kg day) for 14 days resulted in an overall significant reduction in brain 5-HT synthesis. The latter treatment brought the synthesis to the level found in the sham operated rats, i.e., a normal level. These results suggest that normalization (reduction to the level found in the SHX-SAL rats) of 5-HT synthesis in the OBX requires a greater dose of buspirone (20 mg/(kg day)) than that needed to produce a desensitization of the 5-HT1A receptors in the sham operated rats (10 mg/(kg day)). This probably indicates that 5-HT1A receptors have different functionality in the OBX rats than that found in the intact or sham operated rats. Furthermore, our results support the hypothesis that 5-HT1A receptors mediate the antidepressant-like effect of 5-HT1A agonists, as the chronic 5-HT1A agonist treatment in the depression model known to be sensitive to antidepressants resulted in the normalization of 5-HT synthesis.

Therapeutic time window and dose dependence of neuroprotective effects of sodium orthovanadate following transient middle cerebral artery occlusion in rats.

Vanadium is widely distributed in the environment and exhibits various biological and physiological effects in the human body. We previously documented the neuroprotective effect of sodium orthovanadate (SOV) against in rodents i.v. injected with 2 ml/kg 50 mM SOV just after the induction of middle cerebral artery occlusion (MCAO; 0 min post-MCAO). To evaluate its potential clinical use, we determined here therapeutic time window (0, 45, and 90 min post-MCAO) and the neuroprotective dose (2 ml/kg, 12.5, 25, 37.5, and 50 mM) of SOV in rats. A single injection of 50 mM SOV at 0 or 45 min post-MCAO produced similar neuroprotective effects, and even 50 mM delivered 90 min post-MCAO exerted significant neuroprotection. Although the maximal neuroprotective effect was obtained at 50 mM SOV, 25 mM injected once and 12.5 mM delivered at 0 and 45 min post-MCAO significantly reduced the infarct volume. We also documented that SOV treatment ameliorates ischemic neuronal cell injury via the activation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK), inhibits serum glucose, and elicits the gradual recovery of regional cerebral blood flow (rCBF) after transient MCAO in rats. To elucidate the important factor(s) involved in the neuronal protection afforded by SOV, we measured Akt and ERK activity, physiological parameters, blood glucose levels, and rCBF following various SOV treatments. In conclusion, Akt activation was the most important factor in SOV-induced neuroprotection; ERK activation, the gradual recovery of rCBF, and decreased blood glucose were weak contributors.

Brain 5-HT synthesis in the Flinders Sensitive Line rat model of depression: an autoradiographic study.

Alterations of serotonin (5-HT) levels and serotonergic transmission have been associated with depression. 5-HT synthesis is an important factor of serotonergic neurotransmission that may also be altered in depression. Many studies of the relationships between brain serotonergic functions and affective disorders have been performed in different animal models. In this study, brain regional 5-HT synthesis was examined using the alpha-[(14)C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method in a genetic rat model of depression, Flinders Sensitive Line (FSL) rats, and was compared to both the Flinders Resistant Line (FRL) rats and the control Sprague-Dawley (SD) rats. The plasma concentration of free tryptophan in the FSL rats was not significantly different (p > 0.05; ANOVA and post-hoc Bonferroni correction) when compared to that of the FRL and SD rats. The FSL rats had significantly lower 5-HT synthesis (one sample two-tailed t-test on the ratio) than both the FRL and SD rats (the mean ratios were 0.78 +/- 0.12 and 0.73 +/- 0.15, respectively). Overall, the 5-HT synthesis in the FRL rats was not significantly different (p > 0.05) from that in the SD rats (one sample two-tailed t-test on the ratio and the mean ratio was 0.93 +/- 0.13). Studies of individual brain structures, such as the raphe nuclei and their many terminal areas, including the nucleus accumbens, cingulate and frontal cortex, hippocampus, amygdala, and thalamus revealed significant reductions (typically 25-50%) in 5-HT synthesis in the FSL rats compared to the non-depressive FRL and SD rats. These results suggest that significantly reduced 5-HT synthesis in the raphe nuclei and limbic areas in FSL rats may contribute to their depressive features.

The tryptophan hydroxylase activation inhibitor, AGN-2979, decreases regional 5-HT synthesis in the rat brain measured with alpha-[14C]methyl-L-tryptophan: an autoradiographic study.

Many experimental conditions are stressful for animals. It is well known that stress induces tryptophan hydroxylase (TPH) activation, resulting in increased serotonin (5-HT) synthesis. In our experimental procedure to measure 5-HT synthesis using alpha-[(14)C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method, the hind limbs of animals are restrained using a loose-fitted plaster cast such that the forelimbs of the animal remain free. The objective of the present investigation was to evaluate the changes, if any, in 5-HT synthesis, after injecting these restrained rats with the TPH activation inhibitor AGN-2979. The effect on regional 5-HT synthesis was studied using the alpha-MTrp autoradiographic method. The hypothesis was that the TPH activation inhibitor would reduce 5-HT synthesis, if TPH activation was induced by this restraint. The rats received injection of AGN-2979 (10 mg/kg, i.p.) or distilled water vehicle (1 mL/kg, i.p.) 1 h prior to tracer administration. The free- and total tryptophan concentrations were not significantly different between the treatment and control groups. The results demonstrate that 5-HT synthesis in AGN-2979 treated rats is significantly decreased (-12 to -35%) in both the raphe nuclei and their terminal areas when compared to the control rats. These findings suggest that restrained conditions, such as those used in our experimental protocol, induce TPH activation resulting in an increased 5-HT synthesis throughout the brain. The reduction in 5-HT synthesis in the AGN-2979 group is not related to a change in the plasma tryptophan. Because there was no activation in the pineal body, the structure having a different isoform of TPH, we can propose that it is only the brain TPH that becomes activated with this specific restraint.

Selective 5-HT1B receptor agonist reduces serotonin synthesis following acute, and not chronic, drug administration: results of an autoradiographic study.

The effects of acute and chronic administration of the serotonin (5-HT)1B agonist CP-93,129, on 5-HT synthesis rates were evaluated using the alpha-[14C]methyl-L-tryptophan (alpha-MTrp) autoradiographic method. In the acute treatment study, CP-93,129 (7 mg/kg) was injected intraperitoneally 30 min before the alpha-MTrp injection (30 microCi over 2 min). A single dose of CP-93,129 caused a significant increase in the synthesis in the median raphe nucleus (MR) without a significant influence on the dorsal raphe nucleus (DR). There was a reduction in 5-HT synthesis in almost all of the projection areas. In the chronic treatment study, CP-93,129 was administered continuously (7 mg/kg/day) for 14 days using an osmotic minipump implanted subcutaneously. The chronic treatment with CP-93,129 did not produce a significant change in 5-HT synthesis in the raphe nuclei nor in the nerve terminal structures, except for the medial frontal bundle and the visual and sensory-motor cortices. The unaltered 5-HT synthesis rates in the chronic treatment study probably reflect a normalization of the synthesis as a result of the desensitization of 5-HT1B autoreceptors and/or heteroreceptors.