Systemic Elevation of n-3 Polyunsaturated Fatty Acids (n-3-PUFA) Is Associated with Protection against Visual, Motor, and Emotional Deficits in Mice following Closed-Head Mild Traumatic Brain Injury.

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration leading to various pathological complications such as motor and sensory (visual) deficits, cognitive impairment, and depression. N-3 polyunsaturated fatty acid (n-3 PUFA) containing lipids are known to be anti-inflammatory, whereas the sphingolipid, ceramide (Cer), is an inducer of neuroinflammation and degeneration. Using Fat1+-transgenic mice that contain elevated levels of systemic n-3 PUFA, we tested whether they are resistant to mild TBI-mediated sensory-motor and emotional deficits by subjecting Fat1-transgenic mice and their WT littermates to focal cranial air blast (50 psi) or sham blast (0 psi, control). We observed that visual function in WT mice was reduced significantly following TBI but not in Fat1+-blast animals. We also found Fat1+-blast mice were resistant to the decline in motor functions, depression, and fear-producing effects of blast, as well as the reduction in the area of oculomotor nucleus and increase in activated microglia in the optic tract in brain sections seen following blast in WT mice. Lipid and gene expression analyses confirmed an elevated level of the n-3 PUFA eicosapentaenoic acid (EPA) in the plasma and brain, blocking of TBI-mediated increase of Cer in the brain, and decrease in TBI-mediated induction of Cer biosynthetic and inflammatory gene expression in the brain of the Fat1+ mice. Our results demonstrate that suppression of ceramide biosynthesis and inflammatory factors in Fat1+-transgenic mice is associated with significant protection against the visual, motor, and emotional deficits caused by mild TBI. This study suggests that n-3 PUFA (especially, EPA) has a promising therapeutic role in preventing neurodegeneration after TBI.

Neuroprotective effect of hesperidin against emamectin benzoate-induced neurobehavioral toxicity in rats.

Emamectin Benzoate (EMB) is an avermectin insecticide widely used in agriculture and veterinary medicine. Hesperidin (HSP) is a flavanone glycoside predominantly found in citrus fruits and has various beneficial health effects. The current research was conducted to study the neurobehavioral toxic effects of EMB in rats and also to evaluate the protective effect of HSP against these toxic effects. Sixty Sprague-Dawley rats were randomly divided into 4 equal groups: control group, EMB group, HSP group, and EMB + HSP group. EMB (8.8. mg/kg) and/or HSP (100 mg/kg) were administered daily by gavage for 8 weeks. The behavioral assessment demonstrated the adverse effects of EMB on the behavioral, motor, and cognitive brain functions. Exposure to EMB also decreased the activity of antioxidants (catalase and reduced glutathione) and increased the malondialdehyde level in nervous tissue. Moreover, EMB increased the level of inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) and decreased brain-derived neurotrophic factor (BDNF) levels in rats' brains. On the other hand, concurrent administration of HSP ameliorated the toxic effects of EMB as indicated by improvements in neural functions and reduction of oxidative stress and inflammation. The study concluded that exposure to EMB induces toxic effects in the brain of rats and that HSP has a protective effect against these toxic effects.

Aqueous Coriandrum sativum L. extract promotes neuroprotection against motor changes and oxidative damage in rat progeny after maternal exposure to methylmercury.

This study aimed to investigate the effects of Coriandrum sativum aqueous extract (CSAE) on the rat progeny of mothers exposed to methylmercury (MeHg). The presence of bioactive compounds and CSAE's antioxidant capacity been evaluated, and the offspring were assessed for their total mercury levels, motor behavioral parameters and oxidative stress in the cerebellum. The analysis of the bioactive compounds revealed significant amounts of polyphenols, flavonoids, and anthocyanins, as well as a variety of minerals. A DPPH test showed the CSAE had important antioxidant activity. The MeHg + CSAE group performed significantly better spontaneous locomotor activity, palmar grip strength, balance, and motor coordination in behavioral tests compared the MeHg group, as well as in the parameters of oxidative stress, with similar results to those of the control group. The MeHg + CSAE group also had significantly reduced mercury levels in comparison to the MeHg group. Based on the behavioral tests, which detected large locomotor, balance, and coordination improvements, as well as a reduction in oxidative stress, we conclude that CSAE had positive functional results in the offspring of rats exposed to MeHg.

Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia.

INTRODUCTION: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. OBJECTIVE: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. MATERIALS AND METHODS: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. RESULTS: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. CONCLUSION: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Atorvastatin protects GABAergic and dopaminergic neurons in the nigrostriatal system in an experimental rat model of transient focal cerebral ischemia / La atorvastatina protege las neuronas gabérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain regions in a model of transient occlusion of the middle cerebral artery. Materials and methods: Twenty-eight male eight-week-old Wistar rats were used in this study. Both sham and ischemic rats were treated with atorvastatin (10 mg/kg) or carboxymethylcellulose (placebo) by gavage at 6, 24, 48 and 72 hours post-reperfusion. We analyzed the immunoreactivity of glutamic acid decarboxylase and tyrosine hydroxylase in the globus pallidus, caudate putamen and substantia nigra. Results: We observed neurological damage and cell loss in the caudate putamen following ischemia. We also found an increase in tyrosine hydroxylase immunoreactivity in the medial globus pallidus and substantia nigra reticulata, as well as a decrease in glutamic acid decarboxylase immunoreactivity in the lateral globus pallidus in ischemic animals treated with a placebo. However, atorvastatin treatment was able to reverse these effects, significantly decreasing tyrosine hydroxylase levels in the medial globus pallidus and substantia nigra reticulata and significantly increasing glutamic acid decarboxylase levels in the lateral globus pallidus. Conclusion: Our data suggest that post-ischemia treatment with atorvastatin can have neuro-protective effects in exofocal regions far from the ischemic core by modulating the GABAergic and dopaminergic neuronal populations in the nigrostriatal system, which could be useful for preventing neurological disorders.

Introducción. La isquemia cerebral es la tercera causa de muerte y la primera de discapacidad permanente en el mundo. La atorvastatina es un fármaco neuroprotector prometedor para el tratamiento de la apoplejía; sin embargo, su acción sobre las poblaciones neuronales del sistema nigroestriatal después de la isquemia aún se desconoce. Objetivo. Evaluar el efecto de la atorvastatina sobre poblaciones gabérgicas y dopaminérgicas en regiones exofocales en un modelo de oclusión transitoria de la arteria cerebral media. Materiales y métodos. Se utilizaron 28 ratas Wistar macho de ocho semanas de edad. Los ejemplares con isquemia simulada y los ejemplares sometidos a isquemia fueron tratados con atorvastatina (10 mg/kg) y carboximetilcelulosa (placebo) administrados por medio de sonda a las 6, 24, 48 y 72 horas después de la reperfusión. Se analizó la inmunorreacción de la descarboxilasa del ácido glutámico y de la tirosina hidroxilasa en el globo pálido, el putamen caudado y la sustancia negra. Resultados. Los datos confirmaron el daño neurológico y la pérdida celular en el putamen caudado. Se incrementó la inmunorreacción de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata , disminuyendo la inmunorreacción de la descarboxilasa del ácido glutámico en el globo pálido lateral de los animales isquémicos tratados con placebo; sin embargo, el tratamiento con atorvastatina pudo revertirla, lo que logró una disminución significativa de la tirosina hidroxilasa en el globo pálido medial y la sustancia negra pars reticulata y aumentando los niveles de descarboxilasa del ácido glutámico en el globo pálido lateral. Conclusión. Nuestros datos sugieren que la atorvastatina en el tratamiento posterior a la isquemia ejerce neuroprotección en las zonas exofocales, modulando las poblaciones neuronales gabérgicas y dopaminérgicas del sistema nigroestriatal, lo que podría prevenir trastornos neurológicos.

Role of NADPH oxidase in total salvianolic acid injection attenuating ischemia-reperfusion impaired cerebral microcirculation and neurons: implication of AMPK/Akt/PKC.

OBJECTIVE: TSI is a new drug derived from Chinese medicine for treatment of ischemic stroke in China. The aim of this study was to verify the therapeutic effect of TSI in a rat model of MCAO, and further explore the mechanism for its effect. METHODS: Male Sprague-Dawley rats were subjected to right MCAO for 60 minutes followed by reperfusion. TSI (1.67 mg/kg) was administrated before reperfusion via femoral vein injection. Twenty-four hours after reperfusion, the fluorescence intensity of DHR 123 in, leukocyte adhesion to and albumin leakage from the cerebral venules were observed. Neurological scores, TTC staining, brain water content, Nissl staining, TUNEL staining, and MDA content were assessed. Bcl-2/Bax, cleaved caspase-3, NADPH oxidase subunits p47(phox)/p67(phox)/gp91(phox), and AMPK/Akt/PKC were analyzed by Western blot. RESULTS: TSI attenuated I/R-induced microcirculatory disturbance and neuron damage, activated AMPK, inhibited NADPH oxidase subunits membrane translocation, suppressed Akt phosphorylation, and PKC translocation. CONCLUSIONS: TSI attenuates I/R-induced brain injury in rats, supporting its clinic use for treatment of acute ischemic stroke. The role of TSI may benefit from its antioxidant activity, which is most likely implemented via inactivation of NADPH oxidase through a signaling pathway implicating AMPK/Akt/PKC.

Low-frequency repetitive TMS plus anodal transcranial DCS prevents transient decline in bimanual movement induced by contralesional inhibitory rTMS after stroke.

BACKGROUND: Low-frequency repetitive transcranial magnetic stimulation (rTMS) over the unaffected motor cortex may improve motor function of the paretic hand after stroke. However, low-frequency rTMS might adversely affect bimanual movement by decreasing transcallosal function. OBJECTIVE: The authors investigated whether combined administration of rTMS and transcranial direct current stimulation (tDCS) prevents deterioration of bimanual movement induced by low-frequency rTMS over the unaffected hemisphere. METHODS: A total of 27 participants with chronic subcortical stroke were randomly assigned to receive either 1 Hz rTMS over the unaffected hemisphere, anodal tDCS over the affected hemisphere, or a combination of rTMS and tDCS. All patients performed a pinching motor-training task after stimulation. Bimanual movement and transcallosal inhibition (TCI) were evaluated after stimulation. RESULTS: rTMS and rTMS-tDCS enhanced the motor training effect on the paretic hand. rTMS decreased bimanual coordination and reduced TCI from the unaffected to the affected hemisphere (TCI(unaff-aff)). rTMS-tDCS changed TCI balance of both hemispheres but did not affect bimanual coordination or TCI(unaff-aff). The change in bimanual coordination was negatively correlated with TCI(unaff-aff). Following stimulation, improvement in the pinch force in the paretic hand was negatively correlated with TCI balance. CONCLUSIONS: Inhibitory rTMS over the unaffected hemisphere transiently caused deterioration of bimanual movements for the current task in stroke patients. This short-term decline was prevented by combined administration of low-frequency rTMS over the unaffected hemisphere and anodal tDCS over the affected hemisphere. These responses to bihemispheric stimulation suggest possible caution and opportunities for the rehabilitation of hand function after stroke.

A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage.

Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.

Short term dietary fish oil supplementation improves motor deficiencies related to reserpine-induced parkinsonism in rats.

Fish oil (FO) supplementation could cause an increase in the concentration of plasmatic free fatty acids and, consequently, could compete with pro-inflammatory arachidonic acid (ARA) derived from brain biomembranes metabolism in the cerebrospinal fluid. Essential fatty acids (EFA) (n-3) have been reported by their antioxidant and neuroprotective properties, and therefore the influence of the FO supplementation on the reserpine-induced motor disorders was studied. Wistar rats were orally treated with FO solution for 5 days, and co-treated with reserpine (R; 1 mg/kg/mL) or its vehicle for 3 days (every other day). Reserpine-induced orofacial dyskinesia and catalepsy (P < 0.05) were prevented by FO (P < 0.05). Biochemical evaluations showed that reserpine treatment increased the lipid peroxidation in the cortex and striatum (P < 0.05), while the FO supplementation prevented this oxidative effect in both brain regions (P < 0.05). Our results showed the protective role of FO in the brain lipid membranes, reinforcing the beneficial effect of n-3 fatty acids in the prevention of degenerative and motor disorders.

Protective effect of Morus alba leaves on haloperidol-induced orofacial dyskinesia and oxidative stress.

Long-term treatment with haloperidol, a typical neuroleptic, induces neurodegeneration caused by excitotoxicity and oxidative stress, which play an important role in the development of orofacial dyskinesia. In the present investigation, an attempt has been made to examine the effect of a concomitant treatment of methanol extract of Morus alba Linn. (Moraceae) leaves (100-300 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) on an animal model of tardive dyskinesia. Rats were treated for 21 days with haloperidol and Morus alba extract; vacuous chewing movements and tongue protrusions were counted. The extract attenuated the increase in vacuous chewing movements and tongue protrusions induced by haloperidol, which were quantified on day 22. The extract showed a marked effect on behavioral parameters altered by haloperidol treatment. Similar treatment with extract attenuated haloperidol-induced lipid peroxidation and nitrite and normalized superoxide dismutase, catalase, and protein in comparison to the control group. The results suggest a protective effect of Morus alba extract against haloperidol-induced orofacial dyskinesia and oxidative stress.

Effect of Hibiscus rosa sinensis on reserpine-induced neurobehavioral and biochemical alterations in rats.

Effect of methanolic extract of Hibiscus rosa sinensis (100-300 mg/kg) was studied on reserpine-induced orofacial dyskinesia and neurochemical alterations. The rats were treated with intraperitoneal reserpine (1 mg/kg, ip) for 3 days every other day. On day 5, vacuous chewing movements and tongue protrusions were counted for 5 min. Reserpine treated rats significantly developed vacuous chewing movements and tongue protrusions however, coadministration of Hibiscus rosa sinensis roots extract (100, 200 and 300 mg/kg, per orally) attenuated the effects. Biochemical analysis of brain revealed that the reserpine treatment significantly increased lipid peroxidation and decreased levels of superoxide dismutase (SOD), catalase (CAT) and glutathione reductase (GSH), an index of oxidative stress process. Coadministration of extract significantly reduced the lipid peroxidation and reversed the decrease in brain SOD, CAT and GSH levels. The results of the present study suggested that Hibiscus rosa sinensis had a protective role against reserpine-induced orofacial dyskinesia and oxidative stress.

Invasive cortical stimulation to promote recovery of function after stroke: a critical appraisal.

BACKGROUND AND PURPOSE: Residual motor deficits frequently linger after stroke. Search for newer effective strategies to promote functional recovery is ongoing. Brain stimulation, as a means of directing adaptive plasticity, is appealing. Animal studies and Phase I and II trials in humans have indicated safety, feasibility, and efficacy of combining rehabilitation and concurrent invasive cortical stimulation. However, a recent Phase III trial showed no advantage of the combination. We critically review results of various trials and discuss the factors that contributed to the distinctive result. SUMMARY OF REVIEW: Regarding cortical stimulation, it is important to determine the (1) location of peri-infarct representations by integrating multiple neuroanatomical and physiological techniques; (2) role of other mechanisms of stroke recovery; (3) viability of peri-infarct tissue and descending pathways; (4) lesion geometry to ensure no alteration/displacement of current density; and (5) applicability of lessons generated from noninvasive brain stimulation studies in humans. In terms of combining stimulation with rehabilitation, we should understand (1) the principle of homeostatic plasticity; (2) the effect of ongoing cortical activity and phases of learning; and (3) that subject-specific intervention may be necessary. CONCLUSIONS: Future cortical stimulation trials should consider the factors that may have contributed to the peculiar results of the Phase III trial and address those in future study designs.

Preventive effects of genistein on motor dysfunction following 6-hydroxydopamine injection in ovariectomized rats.

Estrogen and phytoestrogens such as the isoflavones have received considerable attention in Parkinson's disease (PD) research. Because they have been reported to possess neuroprotective effects on dopaminergic neurons in the substantia nigra (SN), isoflavones appear particularly promising for post-menopausal women at risk for PD. However, most previous studies were limited to morphological investigation, and the preventive effects of isoflavones on motor function have not been evaluated. The aim of the present study was to elucidate the prevention by an isoflavone against motor dysfunction after injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of ovariectomized rats, which mimics post-menopausal status in women. Pretreatment with genistein, an isoflavone, significantly preserved motor function in rats injected with low-dose 6-OHDA, as evaluated by the stepping and cylinder tests. An estrogen receptor antagonist, ICI182780, reversed the effects of genistein, indicating that this effect of genistein is mediated through estrogen receptors. The functional effects of genistein were accompanied by preservation of tyrosine hydroxylase-immunoreactive neurons in the SN after injection of low-dose 6-OHDA. These findings suggest that genistein may be useful for the prevention of PD in post-menopausal women.

Humanin is a novel neuroprotective agent against stroke.

BACKGROUND AND PURPOSE: Humanin (HN) is a 24-amino acid peptide best known for its ability to protect neurons from damage caused by Alzheimer disease-related proteins. This study examines the neuroprotective effects of HNG (a potent form of HN) on focal cerebral ischemia/reperfusion injury in mice. METHODS: Mice underwent middle cerebral artery occlusion for 75 minutes followed by 24-hour reperfusion. Mice were pretreated with 0.1 microg HNG (intracerebroventricularly) 30 minutes before ischemia; posttreated at 0, 2, 4, and 6 hours after ischemia; or pretreated with 1 microg HNG (intraperitoneally) 1 hour before ischemia. Neurological deficits and cerebral infarct volume were evaluated. Neuronal apoptosis and activated poly(ADP-ribose) polymerase expression were measured by TUNEL and Western blot analysis, respectively. Activated ERKs were examined by Western blot analysis. RESULTS: Pretreatment with 0.1 microg HNG (intracerebroventricularly) 30 minutes before ischemia reduced cerebral infarct volume from 56.2+/-3.0% to 26.1+/-1.4% (P<0.01). HNG posttreatment after 4 hours of reperfusion reduced cerebral infarct volume to 45.6+/-2.6% (P<0.05). Pretreatment with 1 microg HNG (intraperitoneally) 1 hour before ischemia or posttreatment after 2 hours of reperfusion reduced cerebral infarct volume significantly. HNG also significantly improved neurological function and inhibited both neuronal apoptosis as well as poly(ADP-ribose) polymerase activation. A significant decrease of phospho-ERK was observed in mice treated with HNG, whereas phospho-JNK and phospho-p38 levels were not altered. CONCLUSIONS: Our results demonstrate that HNG protects against cerebral ischemia/reperfusion injury in mice. HNG offers neuroprotection in vivo at least in part by inhibiting ERK activation. These findings suggest a potential therapeutic role for HNG in the treatment of stroke.

Valproic acid prevents brain injury in a canine model of hypothermic circulatory arrest: a promising new approach to neuroprotection during cardiac surgery.

BACKGROUND: The anticonvulsant valproic acid (sodium valproate, Depacon) acts as a neuroprotectant in rodents, but has never been tested in larger animals. We used valproate in our canine model of hypothermic circulatory arrest to evaluate its neuroprotective benefit in complex cardiac surgical cases. METHODS: Thirteen dogs pretreated with valproate before 2 hours of hypothermic circulatory arrest survived for 24 hours (n = 7) or 72 hours (n = 6). Thirteen control animals (placebo only) also survived for 24 hours (n = 7) or 72 hours (n = 6) after hypothermic circulatory arrest. Blinded clinical neurologic evaluation was performed daily until sacrifice using the Pittsburgh Canine Neurologic Scoring System. Brains were harvested for blinded histopathologic analysis by a neuropathologist to determine the extent of apoptosis and necrosis in 11 brain regions (Total Brain Cell Death Score: 0 = normal, 99 = extensive neuronal death in all regions). Quantification of N-acetyl-aspartate, an established marker for brain injury, was performed with mass spectrometry. RESULTS: Valproate dogs scored significantly better than control animals on clinical neurologic evaluation. Histopathologic examination revealed that valproate animals demonstrated less neuronal damage (by Total Brain Cell Death Score) than control animals at both 24 hours (16.4 versus 11.4; p = 0.03) and 72 hours (21.7 versus 17.7; p = 0.07). At 72 hours, the entorhinal cortex, an area involved with learning and memory, was significantly protected in valproate dogs (p < 0.05). Furthermore, the cortex, hippocampus, and cerebellum demonstrated preservation of near-normal N-acetyl-aspartate levels after valproate pretreatment. CONCLUSIONS: These data demonstrate clinical, histologic, and biochemical improvements in dogs pretreated with valproate before hypothermic circulatory arrest. This commonly used drug may offer a promising new approach to neuroprotection during cardiac surgery.

[The participation of glutaminergic transmission in the mechanism of movement disorders induced by reverse rotation in white mice]. / Uchastie glutamatergicheskoi peredachi v mekhanizme dvigatel'nykh narushenii, vyzvannykh reversivnym vrashcheniem belykh myshei.

Administration of MK-801 or IEM-1754 prevented akinesia in mice induced by reversing rotation, not less effectively than scopolamine. Quaternary adamantane derivative IEM-1857 was ineffective. IEM-1925 enhanced the locomotor disturbance induced by reversing rotation due, probably, to different spectrum of its antiglutamate action. The data obtained suggest involvement of glutamate synaptic transmission in development of locomotor disturbances of a vestibular origin.

Opposite motor effects of pallidal stimulation in Parkinson's disease.

We studied the effects--on parkinsonian signs, on levodopa-induced dyskinesias, and on levodopa response--of acute experimental high-frequency stimulation of the internal pallidum (GPi) during off-drug and on-drug phases. Thirteen quadripolar electrodes were evaluated in 8 patients with Parkinson's disease (PD). Stimulation of the most ventral contacts, lying at the ventral margin of or just below the GPi, led to pronounced improvement in rigidity and a complete arrest of levodopa-induced dyskinesias. The antiakinetic effect of levodopa was also blocked and the patients became severely akinetic. Stimulation of the most dorsal contacts, lying at the dorsal border of the GPi or inside the external pallidum, usually led to moderate improvement of off-drug akinesia and could also induce dyskinesias in some patients. When using an intermediate contact for chronic stimulation, a good compromise between these opposite effects was usually obtained, mimicking the effect of pallidotomy. We conclude that there are at least two different functional zones within the globus pallidus, at the basis of a different pathophysiology of the cardinal symptoms of PD. The opposite effects may explain the variable results of pallidal surgery reported in the literature and may also largely explain the paradox of PD surgery. A possible anatomical basis for these differential functional effects could be a functional somatotopy within the GPi, with the segregation of the pallidofugal fibers from the outer portion of the GPi, on one hand, forming the ventral ansa lenticularis and from the inner portion of the GPi, on the other hand, forming the dorsal lenticular fasciculus.

Riluzole reduces incidence of abnormal movements but not striatal cell death in a primate model of progressive striatal degeneration.

Riluzole has been shown recently to increase life expectancy in patients with amyotrophic lateral sclerosis. A number of experimental studies also suggest that this compound may be a neuroprotectant. We have investigated in baboons whether riluzole would protect striatal neurons from a prolonged 3-nitropropionic acid (3NP) treatment and ameliorate the associated motor symptoms. In animals receiving 3NP and the solvent of riluzole, 12 weeks of high-dose 3NP treatment resulted in the appearance of persistent leg dystonia and significant increases in the incidence of three categories of abnormal movements and in the dyskinesia index in the apomorphine test (0.5 mg/kg i.m.). Quantitative assessment of these behavioral deficits using a video movement analysis system demonstrated a significant decrease in locomotor activity and peak tangential velocity in 3NP-treated animals compared to controls. Histological analysis showed the presence of severe, bilateral, striatal lesions, localized in both caudate and putamen. Cotreatment with riluzole (4 mg/kg i.p., twice daily) significantly reduced the dyskinesia index (-35%, P < 0.02) in the apomorphine test. In the quantitative behavioral analysis, riluzole significantly ameliorated the decrease in peak tangential velocity (P < 0.02) but not the decrease in locomotor activity observed after 3NP. Comparative histological analysis of the two groups of treated animals did not demonstrate a clear neuroprotective effect of riluzole. The present study suggests that one potential therapeutic interest for riluzole in neurodegenerative disorders may reside in the reduction of motor symptoms associated with striatal lesions.

Long-term thalamic stimulation in Parkinson's disease: postmortem anatomoclinical study.

Parkinsonian tremor may be suppressed by thalamic stimulation. For an equivalent clinical efficacy, its obvious advantage over micro-thalamotomy is its reversibility. This patient experienced postural tremor at the age of 44 years and akineto-rigid syndrome 8 years later. At the age of 60 years, intrathalamic stimulation was applied over a long-term period of 43 months until death and was efficient on tremor with low stimulation. This case is the first with anatomic verification. The extent of the lesion provoked by the electrode is very small. The location of the stimulation site was in the medio-inferior part of the intermedius complex at the entrance of cerebello-thalamic fibers. The stimulation of the cerebellar afferent axons could be the cause of the clinical effect. The stimulation site corresponds to the thalamic source of the precentral and accessory motor cortex, which correlates with changes observed in our PET study showing a regional cerebral blood flow decrease in cerebellar nuclei and also in precentral and accessory motor cortex. The places and mechanisms of the effects of stimulations and lesions could be different.