Effects of Combined Bushen Zhichan Recipe and Levodopa in a Rodent Model of Parkinson Disease: Potential Mechanisms.

BACKGROUND Parkinson disease is characterized by the loss of neurons in the substantia nigra, and under pathological conditions, glutamate can produce excitotoxic effects on nerve cells. The astrocytic excitatory amino acid transporter (EAAT) 1 can be functionally upregulated and targeted to functional compartments, resulting in reduced excitotoxicity. levodopa is the gold standard for the treatment of Parkinson disease, but prolonged levodopa treatment often leads to the development of abnormal involuntary movements. Numerous studies suggest the potential beneficial effects of traditional Chinese medicine on Parkinson disease. MATERIAL AND METHODS We validated the efficacy of a Bushen Zhichan recipe combined with levodopa in a rodent Parkinson disease model and explored its possible mechanisms. RESULTS Rats in the combined levodopa and Bushen Zhichan recipe group performed significantly better than the control group in the open field and forelimb function experiments. The number of midbrain dopaminergic neurons in rats in the levodopa and Bushen Zhichan recipe group was greater compared to controls. The levodopa and Bushen Zhichan recipe group exhibited decreased glutamate receptors and increased γ-aminobutyric acid receptors in the striatum. At the same time, EAAT1 was increased and EAAT2 was synchronized with the number of glutamate receptors. CONCLUSIONS Our results indicate that levodopa combined with Bushen Zhichan recipe significantly improves behavior and protects dopaminergic neurons in a rodent Parkinson disease model, and suggest that the mechanism involves the decrease of excitatory amino acid toxicity and the increase in the expression of EAAT1.

Evaluation of the effects of commonly used α2-adrenergic receptor agonists alone and in combination with butorphanol tartrate on objective measurements of lameness in horses.

OBJECTIVE: To determine the effects of 3 α2-adrenergic receptor agonists (α2-ARAs), alone or in combination with butorphanol tartrate, on objective measurements of lameness in horses. ANIMALS: 17 adult polo horses with naturally occurring forelimb or hind limb lameness (or both). PROCEDURES: In a crossover design, each horse received each protocol (saline [0.09% NaCl] solution [2 mL, IV] or xylazine hydrochloride [0.33 mg/kg, IV], detomidine hydrochloride [0.007 mg/kg, IV], or romifidine hydrochloride [0.033 mg/kg, IV] alone or in combination with butorphanol [0.007 mg/kg, IV]) in random order, with a washout period (≥ 7 days) between protocols. Horses were assessed immediately prior to (baseline) and 10, 15, 20, 30, and 40 minutes after administration of each protocol for degree of sedation, mechanical nociceptive threshold (MNT), and objective lameness measurements. RESULTS: Compared with baseline values, sedation scores and MNTs were significantly higher at all evaluated time points following administration of all sedation protocols except xylazine alone; following administration of xylazine alone, sedation scores and MNTs were significantly higher at ≤ 30 minutes and ≤ 20 minutes, respectively. Significant differences in objective forelimb lameness measurements were noted after administration of the 3 α2-ARA-butorphanol combinations. Most significant differences in objective measurements of hind limb lameness were detected after administration of detomidine or romifidine, alone or in combination with butorphanol. CONCLUSIONS AND CLINICAL RELEVANCE: In the study horses, xylazine alone had the least impact on objective lameness measurements. The administration of α2-ARAs, particularly detomidine or romifidine, alone or in combination with butorphanol, resulted in small but significant effects on objective lameness measurements.

Clinically Relevant Levels of 4-Aminopyridine Strengthen Physiological Responses in Intact Motor Circuits in Rats, Especially After Pyramidal Tract Injury.

BACKGROUND: 4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. OBJECTIVE: To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. METHODS: In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. RESULTS: We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. CONCLUSION: Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.

Causal Link between the Cortico-Rubral Pathway and Functional Recovery through Forced Impaired Limb Use in Rats with Stroke.

Intensive rehabilitation is believed to induce use-dependent plasticity in the injured nervous system; however, its causal relationship to functional recovery is unclear. Here, we performed systematic analysis of the effects of forced use of an impaired forelimb on the recovery of rats after lesioning the internal capsule with intracerebral hemorrhage (ICH). Forced limb use (FLU) group rats exhibited better recovery of skilled forelimb functions and their cortical motor area with forelimb representation was restored and enlarged on the ipsilesional side. In addition, abundant axonal sprouting from the reemerged forelimb area was found in the ipsilateral red nucleus after FLU. To test the causal relationship between the plasticity in the cortico-rubral pathway and recovery, loss-of-function experiments were conducted using a double-viral vector technique, which induces selective blockade of the target pathway. Blockade of the cortico-rubral tract resulted in deficits of the recovered forelimb function in FLU group rats. These findings suggest that the cortico-rubral pathway is a substrate for recovery induced by intensive rehabilitation after ICH. SIGNIFICANCE STATEMENT: The research aimed at determining the causal linkage between reorganization of the motor pathway induced by intensive rehabilitative training and recovery after stroke. We clarified the expansion of the forelimb representation area of the ipsilesional motor cortex by forced impaired forelimb use (FLU) after lesioning the internal capsule with intracerebral hemorrhaging (ICH) in rats. Anterograde tracing showed robust axonal sprouting from the forelimb area to the red nucleus in response to FLU. Selective blockade of the cortico-rubral pathway by the novel double-viral vector technique clearly revealed that the increased cortico-rubral axonal projections had causal linkage to the recovery of reaching movements induced by FLU. Our data demonstrate that the cortico-rubral pathway is responsible for the effect of intensive limb use.

CXCR4 antagonist AMD3100 reverses the neurogenesis and behavioral recovery promoted by forced limb-use in stroke rats.

PURPOSE: Forced limb-use can enhance neurogenesis and behavioral recovery as well as increasing the level of stromal cell-derived factor-1 (SDF-1) in stroke rats. We examined whether the SDF-1/CXCR4 pathway is involved in the enhanced neurogenesis and promoted behavioral recovery induced by forced limb-use in the chronic phase of stroke. METHODS: The CXCR4 antagonist, AMD3100, was used to block the SDF-1/CXCR4 pathway in the ischemic rats. Brain ischemia was induced by endothelin-1. One week after ischemia, the unimpaired forelimb of rats was immobilized for 3 weeks. The proliferation, migration, and survival of DCX-positive cells in the subventricular zone (SVZ), and the dendritic complexity of DCX-positive cells in the dentate gyrus (DG), as well as the inflammatory response in the infarcted striatum were analyzed by immunohistochemistry. Functional recovery was assessed in beam-walking and water maze tests. RESULTS: Forced limb-use enhanced the proliferation, migration, dendritic complexity and the survival of newborn neurons. Furthermore, forced limb-use suppressed the inflammatory response and improved both motor and cognitive functions after stroke. AMD3100 significantly abrogated the enhanced neurogenesis and behavioral recovery induced by forced limb-use without influencing the inflammatory response. CONCLUSIONS: SDF-1/CXCR4 pathway seems to be involved in the enhancement of neurogenesis and behavioral recovery induced by post-stroke forced limb-use.

RING-finger type E3 ubiquitin ligase inhibitors as novel candidates for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) significantly affects quality of life. We recently cloned synoviolin, a RING-type E3 ubiquitin ligase implicated in the endoplasmic reticulum-associated degradation (ERAD) pathway. Synoviolin is highly expressed in rheumatoid synovial cells and may be involved in the pathogenesis of RA. Inhibition of synoviolin activity is a potentially useful therapeutic approach for the treatment of RA. We conducted a high-throughput screen of small molecules to find inhibitors of synoviolin autoubiquitination activity. We identified two classes of small molecules, named LS-101 and LS-102, which inhibited synoviolin activity. LS-102 selectively inhibited synoviolin enzymatic activity, while LS-101 inhibited a broad array of RING-type E3 ligases. Moreover, these inhibitors suppressed the proliferation of rheumatoid synovial cells, and significantly reduced the severity of disease in a mouse model of RA. Our results suggest that inhibition of synoviolin is a potentially useful approach in the treatment of RA.

Effects of progesterone and testosterone on ICH-induced brain injury in rats.

Studies have shown that progesterone reduces brain injury, whereas testosterone increases lesion size after ischemic stroke. This study examined the effects of progesterone and testosterone on intracerebral hemorrhage (ICH)-induced brain injury. Male Sprague-Dawley rats received an injection of 100 µL autologous whole blood into the right basal ganglia. Progesterone (16 mg/kg), testosterone (15 mg/kg) or vehicle was given intraperitoneally 2 h after ICH. Behavioral tests were performed, and the rats were killed after 24 h for brain edema measurement. Perihematomal brain edema was reduced in progesterone-treated rats compared to vehicle-treated rats (p<0.05). Progesterone also improved functional outcome following ICH (p<0.05). Testosterone treatment did not affect perihematomal edema formation, but resulted in lower forelimb placing score (p<0.05). In conclusion, progesterone can reduce brain edema and improve functional outcome, whereas testosterone may have a deleterious effect after ICH in male rats.

Injectable caltrop fruit saponin protects against ischemia-reperfusion injury in rat brain.

The present study aimed to investigate the protective effects of injectable caltrop fruit saponin preparation (ICFSP) on ischemia-reperfusion injury in rat brain. Rats were injected with ICFSP and then subjected to cerebral ischemia-reperfusion injury induced by middle cerebral artery occlusion. Then the neurological deficit score was evaluated by Bederson's method. The infarct size was assessed by TTC staining. The content of malondialdehyde (MDA) and nitric oxide (NO), and the activity of superoxide dismutase (SOD) in rat cerebrum were measured with kits, and the content of 6 K prostaglandin F1α (6-K-PGF 1α), thromboxane B2 (TXB2) and endothelin (ET) in blood plasma was measured by radioimmunoassay. The results demonstrated that ICFSP led to a decrease in infarct size (p < 0.01), neurological deficit score (p < 0.05) and plasma content of TXB2 and ET (p < 0.05), and an increase of the plasma level of 6-K-PGF 1α (p < 0.05) and SOD activity in cerebrum, where the MDA and NO content were decreased. The treatment improved forelimb function. ICFSP showed a similar potency compared to that of Ligustrazine hydrochloride parenteral solution (LHPS) and nimodipine (Nim). We concluded that ICFSP protects the brain damage caused by ischemia-reperfusion injury in rats, and this may be closely related to the regulation of reactive oxygen species (MDA and SOD activity) and NO levels in the rat cerebrum, as well as vasoactive factors in the plasma (6-K-PGF 1α, TXB2 and ET).

An essential role for mast cells as modulators of neutrophils influx in collagen-induced arthritis in the mouse.

Mast cells are involved in immune disorders so that many of the proinflammatory and tissue destructive mediators produced by these cells have been implicated in the pathogenesis of rheumatoid arthritis. This scenario prompted us to investigate the correlation between mast cell degranulation and neutrophil influx within the digits and knees joints of arthritic mice assessing what could be the functional role(s) of joint mast cells in the response to collagen immunization. DBA/1J mice were submitted to collagen-induced arthritis and disease was assessed on day 21, 32 and 42 post-immunization. Pharmacological treatment with the glucocorticoid prednisolone, commonly used in the clinic, and nedocromil, a mast cell stabilizer, was performed from day 21 to 30. Arthritis develop after immunization, gradually increased up to day 42. Neutrophil infiltration peaked on day 32 and 21, in the digits and knees, respectively, showing an unequal pattern of recruitment between these tissues. This difference emerged for mast cells: they peaked in the digits on day 21, but a higher degree of degranulation could be measured in the knee joints. Uneven modulation of arthritis occurred after treatment of mice with prednisolone or nedocromil. Neutrophils migration to the tissue was reduced after both therapies, but only prednisolone augmented mast cell migration to the joints. Nedocromil exerted inhibitory properties both on mast cell proliferation and migration, more effectively on the digit joints. Thus, collagen induced an inflammatory process characterized by tissue mast cells activation and degranulation, suggesting a potential driving force in propagating inflammatory circuits yielding recruitment of neutrophils. However, the different degree of affected joint involvement suggests a time-related implication of digits and knees during collagen-induced arthritis development. These results provide evidence for local alterations whereby mast cells contribute to the initiation of inflammatory arthritis and may be targeted in intervention strategies.

Forelimb dyskinesia mediated by high-frequency stimulation of the subthalamic nucleus is linked to rapid activation of the NR2B subunit of N-methyl-D-aspartate receptors.

Dyskinesia is a major side-effect of chronic l-DOPA administration, the reference treatment for Parkinson's disease. High-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates parkinsonian motor symptoms and indirectly improves dyskinesia by decreasing the L-DOPA requirement. However, inappropriate stimulation can also trigger dyskinetic movements, in both human and rodents. We investigated whether STN-HFS-evoked forelimb dyskinesia involved changes in glutamatergic neurotransmission as previously reported for L-DOPA-induced dyskinesias, focusing on the role of NR2B-containing N-methyl-D-aspartate receptors (NR2B/NMDARs). We applied STN-HFS in normal rats at intensities above and below the threshold for triggering forelimb dyskinesia. Dyskinesiogenic STN-HFS induced the activation of NR2B (as assessed by immunodetection of the phosphorylated residue Tyr(1472)) in neurons of the subthalamic nucleus, entopeduncular nucleus, motor thalamus and forelimb motor cortex. The severity of STN-HFS-induced forelimb dyskinesia was decreased in a dose-dependent manner by systemic injections of CP-101,606, a selective blocker of NR2B/NMDARs, but was either unaffected or increased by the non-selective N-methyl-D-aspartate receptor antagonist, MK-801.

Evaluation of two regional anesthetic methods on the front limb of dogs using hyperbaric bupivacaine / Avaliação de dois métodos de bloqueios anestésicos regionais no membro anterior em cães usando bupivacaína hiperbárica

PURPOSE: To evaluate the effects of bupivacaine 0.5 and 0.25 percent in intravenous regional anesthesia (IVRA) and brachial plexus block (BPB), respectively, on anesthesia, motor block and cardiovascular parameters in dogs. METHODS: Fourteen healthy adult dogs averaging 10 kilograms (kg) of body weight. Animals were randomly assigned to receive one of the two treatments IVRA (n=7) or BPB (n=7). All the animals were sedated with acepromazine (0.1 mg/kg intramuscular). To execute the BPB was used an electrical nerve stimulation. Anesthesia, motor block, sedation, cardiovascular and respiratory effects were measured as effect of the treatment. RESULTS: BPA showed superior efficiency and duration of anesthesia (BPB - 456 ± 94 minutes vs IVRA - 138 ± 44) as well as motor block. There only physiologic parameter which change were the systolic pressure in BPB and respiratory rate for both treatments. CONCLUSION: In dogs the 0.25 percent hyperbaric bupivacaine in BPB produces a front limb anesthesia about three times more than the 0.5 percent in IVRA, with ptosis of the limb blocked and little interference in the cardiovascular system but with decrease in respiratory rate.

OBJETIVO: Avaliar os efeitos da bupivacaína 0,5 e 0,25 por cento na anestesia regional endovenosa (IVRA) e no bloqueio do plexo braquial (BPB) respectivamente, na anestesia, bloqueio motor e parâmetros cardiovasculares em cães. MÉTODOS: Foram utilizados 14 cães sadios adultos pesando em média 10 kilos. Animais foram aleatoriamente designados a um de dois tratamentos IVRA (n = 7) ou BPB (n = 7). Todos os animais foram sedados com acepromazina (0,1 mg/kg intramuscular). Para realizar o BPB foi usado um estimulador elétrico nervoso. Anestesia, bloqueio motor, sedação, efeitos cardiovascular e respiratório foram mensurados como efeitos dos respectivos bloqueios. RESULTADOS: O bloqueio BPB demonstrou eficiência superior e maior duração da anestesia (BPB - 456 ± 94 minutos vs IVRA - 138 ± 44 minutos) bem como maior envolvimento motor. Somente a pressão arterial sistólica foi alterada no grupo BPB e a freqüência respiratória em ambos os tratamentos. CONCLUSÃO: Em cães, a bupivacaína 0,25 por cento hiperbárica no grupo BPB produziu uma anestesia do membro anterior três vezes mais longa que a 0,5 por cento no grupo IVRA, com ptose do membro bloqueado e pequena interferência no sistema cardiovascular e com diminuição da freqüência respiratória.

Evaluation of two regional anesthetic methods on the front limb of dogs using hyperbaric bupivacaine.

PURPOSE: To evaluate the effects of bupivacaine 0.5 and 0.25% in intravenous regional anesthesia (IVRA) and brachial plexus block (BPB), respectively, on anesthesia, motor block and cardiovascular parameters in dogs. METHODS: Fourteen healthy adult dogs averaging 10 kilograms (kg) of body weight. Animals were randomly assigned to receive one of the two treatments IVRA (n=7) or BPB (n=7). All the animals were sedated with acepromazine (0.1 mg/kg intramuscular). To execute the BPB was used an electrical nerve stimulation. Anesthesia, motor block, sedation, cardiovascular and respiratory effects were measured as effect of the treatment. RESULTS: BPA showed superior efficiency and duration of anesthesia (BPB - 456 +/- 94 minutes vs IVRA - 138 +/- 44) as well as motor block. There only physiologic parameter which change were the systolic pressure in BPB and respiratory rate for both treatments. CONCLUSION: In dogs the 0.25 % hyperbaric bupivacaine in BPB produces a front limb anesthesia about three times more than the 0.5 % in IVRA, with ptosis of the limb blocked and little interference in the cardiovascular system but with decrease in respiratory rate.

Intact intracortical microstimulation (ICMS) representations of rostral and caudal forelimb areas in rats with quinolinic acid lesions of the medial or lateral caudate-putamen in an animal model of Huntington's disease.

Neurotoxic, cell-specific lesions of the rat caudate-putamen (CPu) have been proposed as a model of human Huntington's disease and as such impair performance on many motor tasks, including skilled forelimbs tasks such as reaching for food. Because the CPu and motor cortex share reciprocal connections, it has been proposed that the motor deficits are due in part to a secondary disruption of motor cortex. The purpose of the present study was to examine the functionality of the motor cortex using intracortical microstimulation (ICMS) following neurotoxic lesions of the CPu. ICMS maps have been shown to be sensitive indicators of motor skill, cortical injury, learning, and experience. Long-evans hooded rats received a sham, a medial, or a lateral CPu lesion using the neurotoxin, quinolinic acid (2,3-pyridinedicarboxylic acid). Two weeks later the motor cortex was stimulated under light ketamine anesthesia. Neither lateral nor medial lesions of the CPu altered the stimulation threshold for eliciting forelimb movements, the type of movements elicited, or the size of the rostral forelimb (RFA) and caudal forelimb areas (CFA) from which movements were elicited. The preservation of ICMS forelimb movement representations (the forelimb map) in rats with cell-specific CPu lesions suggests motor impairments following lesions of the lateral striatum are not due to the disruption of the motor map. Therefore, the impairments that follow striatal cell loss are due either to alterations in circuitry that is independent of motor cortex or to alterations in circuitry afferent to the motor cortex projections.

Effects of pre- and postnatal exposure to chromium picolinate or picolinic acid on neurological development in CD-1 mice.

Chromium picolinate, Cr(pic)3, a popular dietary supplement marketed as an aid in fat loss and lean muscle gain, has also been suggested as a therapy for women with gestational diabetes. The current study investigated the effects of maternal exposure to Cr(pic)3 and picolinic acid during gestation and lactation on neurological development of the offspring. Mated female CD-1 mice were fed diets from implantation through weaning that were either untreated or that contained Cr(pic)3 (200 mg kg(-1) day(-1)) or picolinic acid (174 mg kg(-1) day(-1)). A comprehensive battery of postnatal tests was administered, including a modified Fox battery, straight-channel swim, open-field activity, and odor-discrimination tests. Pups exposed to picolinic acid tended to weigh less than either control or Cr(pic)3-exposed pups, although the differences were not significant. Offspring of picolinic acid-treated dams also appeared to display impaired learning ability, diminished olfactory orientation ability, and decreased forelimb grip strength, although the differences among the treatment groups were not significant. The results indicate that there were no significant effects on the offspring with regard to neurological development from supplementation of the dams with either Cr(pic)3 or picolinic acid.

Reduction of CD4 positive T cells and improvement of pathological changes of collagen-induced arthritis by FTY720.

FTY720 belongs to a new class of immunosuppressants. Little is known about its influence on T cell subtypes and pathological changes in arthritis. Here we illustrated the effect of FTY720 on peripheral T cell subsets and joint damage of collagen-induced arthritis rats. Rats were administered FTY720 or prednisone daily from day 0 to day 28. Body weight, hind paw swelling and arthritis index were measured. Bone destruction was determined by micro-computed tomography and histopathology, and T cell subsets were analyzed by flow cytometry and immunohistochemistry. The results showed that FTY720 inhibited the development of arthritis. Radiological analysis revealed that FTY720 treated collagen-induced arthritic rats had much less joint damage in comparison to untreated collagen-induced arthritic rats. Histological study showed that collagen-induced arthritic rats suffered from inflammatory cell infiltration and synovial hyperplasia in their joints, and FTY720 treatment clearly reduced these pathological changes. Immunohistochemical analysis showed that FTY720 treatment significantly decreased the number of CD4(+) T cells in the synovium of collagen-induced arthritic rats. Collagen-induced arthritic rats appeared to have more CD4(+), but not CD8(+) T cells in their peripheral blood than normal control rats. Following FTY720 treatment, peripheral blood CD3(+) and CD4(+) T cells in collagen-induced arthritic rats were significantly decreased. In conclusion, FTY720 is an effective compound in the treatment of collagen-induced arthritic rats and in reducing CD4(+) T cells in collagen-induced arthritic rats.

A reproductive screening test of feverfew: is a full reproductive study warranted?

Feverfew is currently used in the treatment of migraine and arthritis. It is traditionally contraindicated in pregnancy but there are no studies confirming this warning. An in vivo and in vitro preliminary screen was performed using a rat model: five female rats were orally dosed with 839 mg/kg feverfew daily on either gestation days (GD) 1-8 or 8-15. On GD20, rats were sacrificed and fetuses, placentae and ovaries were collected. The fetuses were weighed and examined for malformations. While maternal weight gain appeared to be reduced, ANCOVA analysis suggested that the difference was due to litter size, rather than treatment. Pre-implantation loss appeared increased but this was not statistically significant in the feverfew GD1-8 group. Fetuses exposed to feverfew from GD8-15 were smaller than ethanol controls perhaps as a result of the increased frequency of runts in treated litters. Feverfew induced toxicity when GD10.5 embryos were cultured for 26 h in rat serum to which extract was added. The results of the present preliminary study suggest that a comprehensive reproductive study of feverfew is warranted.

Gait abnormalities caused by selective anesthesia of the suprascapular nerve in horses.

OBJECTIVE: To assess gait abnormalities associated with selective anesthesia of the suprascapular nerve (SSN) achieved by use of perineural catheterization and thereby determine the function of that nerve as it relates to gait in horses. ANIMALS: 3 adult horses with no preexisting clinically apparent lameness at a walk. PROCEDURE: Each horse was anesthetized; the right SSN was exposed surgically for placement of a perineural catheter to permit delivery of 1 mL of 2% mepivacaine hydrochloride. Six hours after recovery from anesthesia, each horse was videotaped while walking (50-step data acquisition period) before and after administration of mepivacaine. Videotapes were reviewed and the proportion of abnormal steps before and after selective SSN anesthesia was assessed. A step was considered abnormal if a marked amount of scapulohumeral joint instability (ie, lateral luxation of the proximal portion of the humerus) was observed during the weight-bearing phase of the stride. RESULTS: Clinically apparent gait dysfunction was detected in all 3 horses following perineural administration of the local anesthetic agent. Anesthesia of the SSN resulted in scapulohumeral joint instability as evidenced by consistent lateral excursion of the shoulder region during the weight-bearing phase of gait at a walk. The proportion of abnormal steps before and after SSN anesthesia was significantly different in all 3 horses. CONCLUSIONS AND CLINICAL RELEVANCE: These data support the role of the SSN in shoulder joint stability in horses and define SSN dysfunction as 1 mechanism by which the syndrome and gait dysfunction clinically referred to as sweeny may develop.

Dietary supplementation of omega-3 polyunsaturated fatty acids worsens forelimb motor function after intracerebral hemorrhage in rats.

Dietary intake of omega-3 polyunsaturated fatty acids has been associated with decreased clotting ability and increased risk of hemorrhagic stroke. The aim of the current study was to assess the effect of dietary supplementation of omega-3 polyunsaturated fatty acid on functional outcome after hemorrhagic stroke. Rats were maintained on a diet containing approximately 30% of energy as either fish oil (rich in omega-3 fatty acids) or safflower oil (rich in omega-6 fatty acids) and subjected to either intracerebral hemorrhage or sham surgery. Behavioral tests, infarct measurement, and MR imaging techniques were used to assess outcome. While there was no significant difference in infarct volume between rats on different diets, animals maintained on a diet enriched with fish oil exhibited increased cerebral blood flow after surgery. These animals were significantly more impaired than rats fed the safflower-oil-enriched diet in tests of forelimb dexterity and fine motor control. These results suggest that high intake of omega-3 polyunsaturated fatty acids may not only increase the risk of hemorrhagic stroke as shown in previous studies, but most importantly may lead to a more severe motor impairment and a poorer functional outcome after such an event.

Protection from ethanol-induced limb malformations by the superoxide dismutase/catalase mimetic, EUK-134.

Based on previous in vitro studies that have illustrated prevention of ethanol-induced cell death by antioxidants, using an in vivo model, we have tested the anti-teratogenic potential of a potent synthetic superoxide dismutase plus catalase mimetic, EUK-134. The developing limb of C57BL/6J mice, which is sensitive to ethanol-induced reduction defects, served as the model system. On their ninth day of pregnancy, C57BL/6J mice were administered ethanol (two intraperitoneal doses of 2.9 g/kg given 4 h apart) alone or in combination with EUK-134 (two doses of 10 mg/kg). Pregnant control mice were similarly treated with either vehicle or EUK-134, alone. Within 15 h of the initial ethanol exposure, excessive apoptotic cell death was observed in the apical ectodermal ridge (AER) of the newly forming forelimb buds. Forelimb defects, including postaxial ectrodactyly, metacarpal, and ulnar deficiencies, occurred in 67.3% of the ethanol-exposed fetuses that were examined at 18 days of gestation. The right forelimbs were preferentially affected. No limb malformations were observed in control fetuses. Cell death in the AER of embryos concurrently exposed to ethanol and EUK-134 was notably reduced compared with that in embryos from ethanol-treated dams. Additionally, the antioxidant treatment reduced the incidence of forelimb malformations to 35.9%. This work illustrates that antioxidants can significantly improve the adverse developmental outcome that results from ethanol exposure in utero, diminishing the incidence and severity of major malformations that result from exposure to this important human teratogen.

Interactions between inputs from adjacent digits in somatosensory thalamus and cortex of the raccoon.

Interactions between somatosensory afferents arriving from different points in the periphery play an important role in sensory discrimination and also provide the substrate for plasticity following peripheral injury. To examine the extent and time course of such interactions, extracellular recordings were made from neurons in the primary somatosensory cortex and the ventroposterior lateral thalamus of anesthetized raccoons. Interactions between adjacent digits were studied using the conditioning-test paradigm in which a test pulse was delivered to the digit containing the neuron's receptive field (the on-focus digit) at various intervals following conditioning stimulation of an adjacent, off-focus digit. Off-focus stimulation produced predominantly inhibition of the test response with a maximum effect at 20-40 ms in both cortex and thalamus. The mean inhibition was approximately twice as large in the thalamus as in the cortex. Recordings were made in other animals after unmyelinated C fibers had been destroyed in the on-focus digit by subcutaneous injection of capsaicin. This resulted in a doubling of the responses evoked by the test stimulus in both regions, but the spontaneous discharge rate was not changed. The amount of inhibition produced in the cortex was unchanged by capsaicin treatment, but was reduced in the thalamus compared to control animals. This indicates that capsaicin-sensitive peripheral afferents provide a tonic control over interdigit inhibition in the thalamus.