Tantalum Cones for Severe Bone Defects in Revision Knee Arthroplasty: A Minimum 10-Year Follow-Up.

BACKGROUND: Two-to 6-year results of reconstruction of severe bone defects in revision total knee arthroplasty (TKA) with highly porous tantalum cones have been encouraging, but 10-year follow-up is lacking. The purpose of this study was to determine the minimum 10-year results of tantalum cones in revision TKA. METHODS: From 2005 to 2010, 30 consecutive patients (30 knees) underwent revision TKA with the use of cones. All patients were followed clinically and radiographically for a minimum of 10 years. A total of 42 cones (25 tibial and 17 femoral) were used to reconstruct massive bone defects classified as Anderson Orthopaedic Research Institute Types 2A (10), 2B (12), and 3 (19). The mean age of the patients was 73 years (range, 55 to 84) at the time of revision. The indication for the revision included aseptic loosening (15 patients) and second-stage reimplantation for deep infection (15 patients). Six patients were lost to follow-up. RESULTS: In total, 6 cones had to be revised. Minimum 10-year cone survivorship for any reason was 81% (25 of 31 cones). With cone revision for aseptic loosening as the end point, survivorship was 96% (30 of 31). No evidence of loosening or migration of any implant was noted on the most recent radiographs. CONCLUSION: Metaphyseal fixation with tantalum cones in revision TKA demonstrated excellent survivorship and fixation at a minimum follow-up of 10 years. This type of metaphyseal reconstruction can be a durable option for revision TKA in patients who have massive bone defects.

Survivorship and clinical outcomes of proximal femoral replacement in non-neoplastic primary and revision total hip arthroplasty: a systematic review.

BACKGROUND: Several studies have evaluated the survivorship and clinical outcomes of proximal femoral replacement (PFR) in complex primary and revision total hip arthroplasty with severe proximal femoral bone loss; however, there remains no consensus on the overall performance of this implant. We therefore performed a systematic review of the literature in order to examine survivorship and complication rates of PFR usage. METHODS: A systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. A comprehensive search of PubMed, MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews was conducted for English articles using various combinations of keywords. RESULTS: In all, 18 articles met the inclusion criteria. A total of 578 PFR were implanted. The all-cause reoperation-free survivorship was 76.6%. The overall complication rate was 27.2%. Dislocation was the most common complication observed and the most frequent reason for reoperation with an incidence of 12.8 and 7.6%, respectively. Infection after PFR had an incidence of 7.6% and a reoperation rate of 6.4%. The reoperation rate for aseptic loosening of the implant was 5.9%. Overall, patients had improved outcomes as documented by postoperative hip scores. CONCLUSION: PFR usage have a relatively high complication rate, however, it remains an efficacious treatment option in elderly patients with osteoporotic bone affected by severe proximal femoral bone loss. Modular designs have shown reduced dislocations rate and higher survivorship free from dislocation. However, PFR should only be used as salvage procedure when no other reconstruction options are available.

Results of Utilizing Cerclage Wires in the Management of Intraoperative Vancouver B1 Fractures in Primary Total Hip Arthroplasties: A Retrospective Cohort Investigation into Clinical and Radiographic Outcomes.

BACKGROUND: Due to an increase in total hip arthroplasties (THAs), the incidence of periprosthetic hip fractures (PPHFs) is forecast to rise considerably in the next decades, with Vancouver B1 fractures (VB1) accounting for one third of total cases. Femur fixation with cerclages (with or without screws) is considered the current treatment option for intraoperative VB1. METHODS: The study retrospectively includes data from patients who developed VB1 PPHFs during THAs from 3 December 2020 to 30 November 2022. The primary outcome of this study was to identify the reintervention-free survival rate. The secondary aim was to determine clinical and radiographic assessment at follow-up, based on Harris hip score (HHS) and limb length discrepancy (LLD). RESULTS: Thirty-seven patients with a mean age of 60.03 ± 15.49 (22 to 77) years old were included. Overall, the Kaplan-Meier analysis estimated a reoperation-free survival rate of 99% (CI 95%) at 6 months. The mean limb length discrepancy (LLD) improved from -3.69 ± 6.07 (range -27.9 to 2.08) mm to 0.10 ± 0.67 (range -1.07 to 1.20) mm. The mean HHS improved from 42.72 ± 14.37 (range 21.00-96.00) to 94.40 ± 10.32 (range 56.00-100.00). CONCLUSIONS: The employment of cerclage wires represents an effective strategy for handling intraoperative VB1 fractures. Level III retrospective cohort study.

Using Three-Dimensional Printing Technology to Solve Complex Primary Total Hip Arthroplasty Cases: Do We Really Need Custom-Made Guides and Templates? A Critical Systematic Review on the Available Evidence.

The burden of osteoarthritis (OA) is around 300 million people affected worldwide, with the hip representing a commonly affected joint. Total hip arthroplasty (THA) has been used with notable success as a definitive treatment to improve pain and function in hip OA patients. The recent advent of new technologies, such as 3D printing, has pushed the application of these new concepts toward applications for the well-known THA. Currently, the evidence on the use of 3D printing to aid complex primary THA cases is still scarce. METHODS: An extensive literature review was conducted to retrieve all articles centered on the use of 3D printing in the setting of primary THA. RESULTS: A total of seven studies were included in the present systematic review. Four studies investigated the use of 3D-printed surgical guides to be used during surgery. The remaining three studies investigated the benefit of the use of 3D-printed templates of the pelvis to simulate the surgery. CONCLUSIONS: The use of 3D printing could be a promising aid to solve difficult primary total hip arthroplasty cases. However, the general enthusiasm in the field is not supported by high-quality studies, hence preventing us from currently recommending its application in everyday practice.

Clinical and Radiographic Outcomes of Hip Revision Surgery and Cerclage Wires Fixation for Vancouver B2 and B3 Fractures: A Retrospective Cohort Study.

BACKGROUND: The number of patients presenting with periprosthetic hip fractures has increased in recent decades. METHODS: Patients who underwent hip revision arthroplasty procedures for Vancouver type B2 and B3 fractures between 2010 and 2021 were included. The primary intended outcome of this study was to determine the reintervention-free survival rate. The secondary intended outcome was to determine clinical and radiographic assessment outcomes at the time of follow-up, and the correlation between time to surgery and postoperative Harris hip score (HHS). RESULTS: A total of 49 patients with mean age of 71.2 ± 2.3 (37-88) years old were included. Overall, the Kaplan-Meier method estimated a survival rate of 95.8% (CI 84.2% to 98.9%) at one year, 91.1% (CI 77.9% to 96.6%) at two years, and 88.5% (CI 74.4% to 95.1%) at three, and up to 10, years. The mean limb length discrepancy (LLD) improved from -13.3 ± 10.5 (range -39 to +10) mm at the preoperative stage to -1.16 ± 6.7 (range -17 to +15) mm, p < 0.001 postoperative. The mean HHS improved from 31.1 ± 7.7 (range 10 to 43) preoperative to 85.5 ± 14.8 (range 60 to 100), p < 0.001 postoperative. Postoperative HHS was not affected by preoperative time to surgery. CONCLUSIONS: Revision arthroplasty is an effective treatment for Vancouver type B2 and B3 fractures.

5-HT2 receptors-mediated modulation of voltage-gated K+ channels and neurophysiopathological correlates.

The activity of voltage-gated K(+) channels (Kv) can be dynamically modulated by several events, including neurotransmitter stimulated biochemical cascades mediated by G protein-coupled receptors such as 5-HT2 receptors (5-HT2Rs). Activation of 5-HT2A/CR inhibits the Shaker-like K(+) channels Kv1.1 and Kv1.2, and this modulation involves the dual coordination of both RPTPα and distinct tyrosine kinases coupled to this receptor; 5-HT2Rs-mediated modulation of Kv channels controls glutamate release onto prefrontal cortex neurons that might play critical roles in neurophysiological, neurological, and psychiatric conditions. Noticeably, hallucinogens modulate Kv channel activity, acting at 5-HT2R. Hence, comprehensive knowledge of 5-HT2R signaling through modulation of distinct K(+) channels is a pivotal step in the direction that will enable scientists to discover novel 5-HT functions and dysfunctions in the brain and to identify original therapeutic targets.

Perioperative Complications after Hip and Knee Revision Arthroplasty in the over 80 Years Old Population: A Retrospective Observational Case-Control Study.

BACKGROUND: The number of joint revision arthroplasties has increased in the elderly population, which is burdened by several perioperative risks. METHODS: Patients who underwent hip and knee revision arthroplasty were retrospectively included, and they were divided into two groups by age: <80 years old (Group 1) and ≥80 years old (Group 2). The primary outcome was to compare perioperative complication rates. The secondary outcome was to compare the 30-day, 90-day, and 1-year readmission rates. RESULTS: In total, 74 patients in Group 1 and 75 patients in Group 2 were included. Postoperative anemia affected 13 patients in Group 1 (17.6%) and 25 in Group 2 (33.3%, p 0.027); blood units were transfused in 20 (26.7%) and 11 (14.9%, p 0.076) patients, respectively. In Group 1, two (2.7%) patients reported wound infection. In Group 2, eight (10.7%) patients presented hematomas, and two (2.7%) patients reported dislocations. No significant differences in the two groups were observed for 30-day (p 0.208), 90-day (p 0.273), or 1-year readmission rates (p 0.784). CONCLUSION: The revision arthroplasty procedure in patients over 80 years old is not associated with a higher risk of perioperative complications, or higher readmission rate compared with younger patients undergoing hip and knee revision surgery.

Short-Term Survivorship of 3D-Printed Titanium Metaphyseal Cones in Revision Total Knee Arthroplasty: A Systematic Review.

Background: Several studies have evaluated the outcomes of tantalum cones in revision knee arthroplasty with moderate-to-severe metaphyseal bone defects. However, recent innovations have led to the development of 3-D printed titanium cones to better adapt to host bone, there remains no consensus on their overall performance. Objective: We therefore performed a systematic review of the literature to examine short-term survivorship and complication rates of their usage in revision TKAs. Methods: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive search of PubMed, MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews was conducted for English articles using various combinations of keywords. Results: In all, 7 articles met the inclusion criteria. A total of 687 cones were implanted in 557 revision TKAs. The all-cause revision-free survivorship of the implants was 95.3% (26 revisions), and of the cones was 95.5% (31 cones revised) at mean 24 months follow-up. The cones revision-free survivorship from aseptic loosening was 99.7%. The overall complication rate was 19.7% with infection as the most common complications observed and the most frequent reason for revision with an incidence of 10.4% and 4.1%, respectively. Overall, functional outcomes improved as documented by postoperative knee scores. Conclusion: 3-D printed metal cones represent a reliable option in metaphyseal bone defects reconstruction that provides high fixation, good short-term survivorship, and complications rates in line with similar devices. In addition, they are associated with lower intraoperative complications, and higher survivorship from aseptic loosening.

Mid-term survivorship and clinical outcomes of the medial stabilized systems in primary total knee arthroplasty: A systematic review.

INTRODUCTION: Medial Pivot Total Knee Arthroplasty was introduced in clinical practice in 1990s to reproduce the in vivo-natural knee kinematics. This design is characterized by an asymmetric constraint profile, with aa highly congruent medial compartment, and a less congruent lateral compartment. Short-term outcomes of the medial pivot systems in primary knee arthroplasty have been widely reported in the current literature, however, only few studies have described results beyond 5-year follow-up. OBJECTIVES: The primary objectives of this systematic review of the literature is to analyze the mid-term studies on medial pivot total knee arthroplasty focusing on the reoperation rate, survivorship and clinical outcome scores. METHODS: The US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews were queried for publications from January 1980 to December 2019 utilizing the following keywords: "medial pivot", "medial stabilized", "medial rotating", "medial congruent", medial ball and socket", "arthroplasty", "TKA", "TKR", and "knee surgery". RESULTS: 18 articles met the inclusion criteria for the present study. The average quality was 11.4 for non-comparative studies and 21.7 for comparative studies based on MINORS criteria. A total 2832 knee arthroplasties were included for the final analysis with an average age of 69 years, and an average follow-up of 8.1 years (minimum 5 years). The overall reoperation rate was 2.4%, with periprosthetic joint infection as the leading cause of revision in 0.9% of cases, followed by aseptic loosening in 0.4% of cases. The average Knee Society Score improved to a mean preoperative score of 40.1 to a mean postoperative score of 89.2. The functional knee society score improved from a mean preoperative score of 44.8 to an average postoperative score of 82.9. The global range of motion improved from 104.8° preoperatively to 115.6° postoperatively. CONCLUSION: We found that medial pivot system in primary total knee arthroplasty provide overall mid-term survivorship comparable to other standard implasnts. In addition, medial pivot system is associated with better high-end function compared to standard implants.

Reconstruction options and outcomes for acetabular bone loss in revision hip arthroplasty.

Revision total hip arthroplasty in the setting of acetabular bone loss is a challenging procedure and requires a solid understanding of current acetabular reconstruction options. Despite major developments in the field of revision hip surgery in recent decades, reconstruction of acetabular defects remains a major problem in order to achieve primary stability and durable fixation without sacrificing additional bone stock. Although there are several ways to classify acetabular bone defects, the Paprosky classification system is the most commonly used to describe the defects and guide treatment strategy. An understanding of the bone defects associated with detailed pre-operative assessment and planning are essential elements in order to achieve satisfactory outcomes. Multiple acetabular reconstructive options are currently available including impaction bone grafting with metal mesh, reinforcement rings and antiprotrusio cage, structural allografts, cementless hemispherical cups, extra-large "jumbo cups", oblong cups, modular porous metal augments, cup-cage constructs, custom- made triflange cups, and acetabular distraction. To date, debate continues as to which technique is most effective due to the lack of long-term studies of modern reconstruction systems. Further long-term studies are necessary to assess the longevity of the different implants. The purpose of this study was to review the current literature and provide a comprehensive understanding of the available reconstruction options with their clinical outcomes.

What are the benefits of robotic-assisted total knee arthroplasty over conventional manual total knee arthroplasty? A systematic review of comparative studies.

Total knee arthroplasty (TKA) is a highly successful operation that improves patients' quality of life and functionality. Yet, up to 20% of TKA patients remain unsatisfied with the functional outcomes. Robotic TKA has gained increased attention and popularity in order to improve patient satisfaction and implant survivorship by increasing accuracy and precision of component implantation. The current systematic review was run in order to compare implant survivorship, complication rates, clinical outcomes, and radiological outcomes between robotic-assisted TKA (RA) and conventional manual TKA (CM). Articles were referenced from the US National Library of Medicine (PubMed/MEDLINE), EMBASE, and the Cochrane Database of Systematic Reviews. Nine comparative studies with 1199 operated knees in 1159 patients were included, 614 underwent active or semiactive robotic-assisted TKA compared to 585 CM-TKA. Improvements in the RA group were reported for early functional outcomes, radiographic outliers (RA 16% vs CM 76%) and radiolucent lines (RA 0% vs CM 35%). No significant differences between the two groups were reported in overall survivorship (RA 98.3% vs CM 97.3%), complication rate (RA 2.4% vs CM 1.4%) and operative time (RA 88 min vs CM 79 min). Despite higher costs, roboticassisted TKA offers better short-term clinical outcomes when compared to conventional manual technique with reduction in radiographic outliers and reduced risks of iatrogenic soft tissues injuries (reduced blood loss and postoperative drainage). Further high-quality long-term studies of modern robotic systems are required in order to evaluate how the increased accuracy and reduced outliers affect the long-term survivorship of the implants and the clinical outcomes.

Surgical implications of the hip-spine relationship in total hip arthroplasty.

Total hip arthroplasty (THA) is considered the most successful orthopedic surgical procedure of the last century with excellent survivorship up to 20-years. However, instability remains a major issue representing the most common reason for revision after THA. Hip-spine relationship has gained progressive interest between arthroplasty surgeons and its understanding is crucial in order to identify high-risk patients for postoperative dislocation. Spinal deformity and abnormal spinopelvic mobility have been associated with increased risk for instability, dislocation and revision THA. Preoperative workup begins with standing anteroposterior pelvis x-ray and lateral spinopelvic radiographs in the standing and sitting position. Hip-spine stiffness needs to be addressed before THA in consideration of adapting the preoperative planning to the patient's characteristics. Acetabular component should be implanted with different anteversion and inclination angles according to the pattern of hip-spine motion in order to reduce the risk of impingement and consequent dislocation. Different algorithmic approaches have been proposed in case of concomitant hip-spine disease and in case of altered sagittal balance and pelvic mobility. The aim of this review is to investigate and clarify the hip-spine relationships and evaluate the impact on modern total hip arthroplasty.

In vivo microdialysis in Parkinson's research.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopamine (DA) neurons in the nigrostriatal system, which in turn produces profound neurochemical changes within the basal ganglia, representing the neural substrate for parkinsonian motor symptoms. The pathogenesis of the disease is still not completely understood, but environmental and genetic factors are thought to play important roles. Research into the pathogenesis and the development of new therapeutic intervention strategies that will slow or stop the progression of the disease in human has rapidly advanced by the use of neurotoxins that specifically target DA neurons. Over the years, a broad variety of experimental models of the disease has been developed and applied in diverse animal species. The two most common toxin models used employ 6-hydroxydopamine (6-OHDA) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenilpyridinium ion (MPTP/MPP+), either given systemically or locally applied into the nigrostriatal pathway, to resemble PD features in animals. Both neurotoxins selectively and rapidly destroy catecolaminergic neurons, although with different mechanisms. Since in vivo microdialysis coupled to high-performance liquid chromatography is an established technique for studying physiological, pharmacological, and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid, here we review the most prominent animal and human data obtained by the use of this technique in PD research.

Electrophysiological and neurochemical characterization of 7-nitroindazole and molsidomine acute and sub-chronic administration effects in the dopaminergic nigrostrial system in rats.

Nitric oxide (NO) plays an important role in the integration of information processed by the basal ganglia nuclei. Accordingly, considerable evidence has emerged indicating a role for NO in pathophysiological conditions such as Parkinson's disease (PD) and other neurodegenerative disorders. Despite these recent advances, the nitrergic modulation of the dopamine (DA) nigrostriatal system is still unclear. In order to fill this gap, in this study we used in vivo electrophysiology and ex vivo neurochemical analysis to further investigate the effect of NO signaling in rat substantia nigra pars compacta (SNc) and the striatum. Acute and subchronic (4 days) pharmacological manipulation of the NO system using 7-nitroindazole (7-NI, 50 mg kg(-1) i.p.) and molsidomine (MOL, 40 mg kg(-1) i.p.) treatment caused significant changes in both DA SNc neurons electrophysiological properties and striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. It is worth noting that acute inhibition of NO production decreased DA nigrostriatal neurotransmission while its subchronic inhibition was instead excitatory. Thus, a crucial role for NO in the modulation of nigrostriatal DA function is suggested together with a potential role for inhibitors of NO sythase in the treatment of PD.

Intake of tomato-enriched diet protects from 6-hydroxydopamine-induced degeneration of rat nigral dopaminergic neurons.

There is extensive evidence that oxidative damage of dopamine (DA)-containing neurons in the substantia nigra pars compacta (SNc) may contribute to the pathogenesis of Parkinson's disease (PD). We evaluated the potential neuroprotective effect of diets enriched with wild-type Red Setter (RS) tomato or transgenic High Carotene (HC) tomato, rich in beta-carotene, obtained by the activation of lycopene beta-cyclase (tlcy-b), in an animal model of PD. Male Fischer 344 rats were fed for 14 days with standard Altromin diet, 5% RS- or 5% HC-enriched diet. Seven days after the beginning of this diet regimen, the rats were lesioned by 6-hydroxydopamine (6-OHDA) injected into the left SNc. After further 7 days, the rats were sacrificed, and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both the left (ipsilateral) and the right (contralateral) striata were measured. Striatal DA levels were reduced by 86.5 +/- 5.0% in control, 86.2 +/- 5.0% in HC-, and 56.0 +/- 9.0% in RS-fed group. Striatal DOPAC was decreased by 85.6 +/- 5.0% in controls, 83.0 +/- 6.0% in HC-, and 58.9 +/- 10.0% in RS-fed group. Blood was obtained from the rats on day 14 and the plasma level of licopene and beta-carotene was measured by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) for the determination of lycopene and beta-carotene levels. The plasma level of lycopene was 4.7 +/- 0.2 ng/ml in 5% RS-fed rats, while it was undetectable (< 2.5 ng ml(-1)) in control and HC-fed rats. The efficacy of RS diet to preserve striatal dopaminergic innervation can be attributed to the ability of lycopene to prevent the degeneration of DA-containing neurons in the SNc.

Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential.

The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.

Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2C receptor be a new target for therapeutic strategies?

The basal ganglia are a highly interconnected group of subcortical nuclei in the vertebrate brain that play a critical role not only in the control of movements but also in some cognitive and behavioral functions. Several recent studies have emphasized that serotonergic pathways in the central nervous system (CNS) are intimately involved in the modulation of the basal ganglia and in the pathophysiology of human involuntary movement disorders. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of the basal ganglia. In fact, serotonergic terminals have been reported to make synaptic contacts with dopamine (DA)-containing neurons and gamma-aminobutyric acid (GABA)-containing neurons in the striatum, globus pallidus, subthalamus and substantia nigra. These brain areas contain the highest concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. Furthermore, in these structures a high expression of 5-HT different receptor subtypes has been revealed. In this paper, evidence demonstrating the serotonergic control of basal ganglia functions will be reviewed, focusing on the role of the 5-HT2C receptor subtype. In addition, the involvement of 5-HT2C receptors in neurological disorders such as Parkinson's disease and other related motor disorders, and their management with drugs blocking the 5-HT2C receptor will be discussed.

7-nitroindazole protects striatal dopaminergic neurons against MPP+-induced degeneration: an in vivo microdialysis study.

The neuropathological hallmark of Parkinson's disease (PD) is the selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). In this study, using a microdialysis technique, we investigated whether an inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitrindazole (7-NI), could protect against DAergic neuronal damage induced by in vivo infusion of 1-methyl-4-phenylpiridinium iodide (MPP(+)) in freely moving rats. Experiments were performed over 2 days in three groups of rats: (a) nonlesioned, (b) MPP(+)-lesioned, and (c) 7-NI pretreated MPP(+)-lesioned rats. On day 1, control rats were perfused with an artificial CSF, while 1 mM MPP(+) was infused into the striatum for 10 min in the other two groups. The infusion of the MPP(+) produced a neurotoxic damage of the SNc DA neurons and increased striatal DA levels. On day 2, 1 mM MPP(+) was reperfused for 10 min into the striata of each rat group and DA levels were measured as an index of neuronal cell integrity. The limited rise of DA following MPP(+) reperfusion in the MPP(+)-lesioned rats was due to toxin-induced neuronal loss and was reversed by pretreatment with 7-NI (50 mg/kg, intraperitoneally) on day 1, indicating a neuroprotective effect by inhibiting NO formation. These results indicate that neuronally derived NO partially mediates MPP(+)-induced neurotoxicity. The similarity between the MPP(+) model and PD suggests that NO may play a significant role in its etiology.

Aspirin protects striatal dopaminergic neurons from neurotoxin-induced degeneration: an in vivo microdialysis study.

The effect of aspirin on dopaminergic neuronal damage induced by in vivo infusion of 1-methyl-4-phenylpiridinium iodide (MPP(+)) and 6-hydroxydopamine (6-OHDA) was studied in rats, using microdialysis. Rat striata were perfused with 1 mM MPP(+) or 6-OHDA for 10 min, causing peak levels of dopamine (DA) in the dialytic fluid, after 40 min. After 24 h, 1 mM MPP(+) was perfused again for 10 min and DA levels measured in the dialytic fluid, as an index of neuronal cell integrity. Pretreatment with Aspidol (lysine acetylsalicylate), 180 mg/kg i.p., 1 h before MPP(+) or 6-OHDA perfusion, did not modify DA extracellular output, on day 1, but restored MPP(+)-induced DA release on day 2, indicating a neuroprotective effect of Aspidol. Conversion of 0.5 mM 4-hydroxybenzoic acid (4-HBA) to 3,4-dihydroxybenzoic acid (3,4-DHBA) was measured as an index of reactive oxygen species (ROS). 6-OHDA, but not MPP(+), significantly enhanced 3,4-DHBA levels in the perfusion fluid. Aspidol (180 mg/kg, i.p.) reduced 6-OHDA-dependent increase of 3,4-DHBA levels. Meloxicam (50 mg/kg, i.p.), a specific cyclooxygenase-2 (COX-2) inhibitor, was ineffective against both neurotoxins. These data suggest that the protective effect of aspirin is due to different mechanisms of action according to the neurotoxin used, and it is independent from COX-2 inhibition.

Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain.

The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5-HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene-sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY-181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression.