Manabu Kakinohana

Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson's disease.

Parkinsons disease is one of the major neurodegenerative disorders. Neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can cause Parkinsons disease-like symptoms and biochemical changes in humans and animals. Hydrogen sulfide (H(2)S) has been shown to protect neurons. The goal of this study was to examine the effects of inhaled H(2)S in a mouse model of Parkinsons disease induced by MPTP. Male C57BL/6J mice received MPTP at 80 mg/kg and breathed air with or without 40 ppm H(2)S for 8 h/day for 7 days. Administration of MPTP induced movement disorder and decreased tyrosine hydroxylase (TH)-containing neurons in the substantia nigra and striatum in mice that breathed air. Inhalation of H(2)S prevented the MPTP-induced movement disorder and the degeneration of TH-containing neurons. Inhaled H(2)S also prevented apoptosis of the TH-containing neurons and gliosis in nigrostriatal region after administration of MPTP. The neuroprotective effect of inhaled H(2)S after MPTP administration was associated with upregulation of genes encoding antioxidant proteins, including heme oxygenase-1 and glutamate-cysteine ligase. These observations suggest that inhaled H(2)S prevents neurodegeneration in a mouse model of Parkinsons disease induced by MPTP, potentially via upregulation of antioxidant defense mechanisms and inhibition of inflammation and apoptosis in the brain.

Neuraxial morphine may trigger transient motor dysfunction after a noninjurious interval of spinal cord ischemia : a clinical and experimental study

Background A patient underwent repair of a thoracoabdominal aortic aneurysm. Epidural morphine, 4 mg, was given for pain relief. After anesthesia, the patient displayed lower extremity paraparesis. This effect was reversed by naloxone. The authors sought to confirm these observations using a rat spinal ischemia model to define the effects of intrathecal morphine administered at various times after reflow on behavior and spinal histopathology. Methods Spinal cord ischemia was induced for 6 min using an intraaortic balloon. Morphine or saline, 30 &mgr;g, was injected intrathecally at 0.5, 2, or 24 h after reflow. In a separate group, spinal cord temperature was decreased to 27°C before ischemia. After ischemia, recovery of motor function was assessed periodically using the motor deficit index (0 = complete recovery; 6 = complete paraplegia). Results After ischemia, all rats showed near-complete recovery of function by 4–6 h. Intrathecal injection of morphine at 0.5 or 2 h of reflow (but not at 24 h) but not saline caused a development of hind limb dysfunction and lasted for 4.5 h (motor deficit index score = 4–6). This effect was reversed by intrathecal naloxone (30 &mgr;g). Intrathecal morphine administered after hypothermic ischemia was without effect. Histopathological analysis in animals that received intrathecal morphine at 0.5 or 2 h after ischemia (but not at 24 h) revealed dark-staining &agr; motoneurons and interneurons. Intrathecal saline or spinal hypothermia plus morphine was without effect. Conclusions These data indicate that during the immediate reflow following a noninjurious interval of spinal ischemia, intrathecal morphine potentiates motor dysfunction. Reversal by naloxone suggests that this effect results from an opioid receptor–mediated potentiation of a transient block of inhibitory neurons initiated by spinal ischemia.

Propofol reduces spinal motor neuron excitability in humans.

IMPLICATIONS We investigated in humans whether changes in spinal motor neuron excitability correlate with the predicted propofol concentration (Cpt) achieved by a target-controlled infusion system. Propofol suppressed F-wave persistence in a Cpt-dependent manner, indicating that propofol depresses spinal motor neuron excitability at clinically relevant concentrations.

The Effect of Graded Postischemic Spinal Cord Hypothermia on Neurological Outcome and Histopathology after Transient Spinal Ischemia in Rat

BACKGROUND Previous data have shown that postischemic brain hypothermia is protective. The authors evaluated the effect of postischemic spinal hypothermia on neurologic function and spinal histopathologic indices after aortic occlusion in the rat. METHODS Spinal ischemia was induced by aortic occlusion lasting 10 min. After ischemia, spinal hypothermia was induced using a subcutaneous heat exchanger. Three studies were conducted. In the first study, the intrathecal temperature was decreased to 34, 30, or 27 degrees C for 2 h beginning with initial reperfusion. In the second study, hypothermia (target intrathecal temperature 27 degrees C) was initiated with reflow and maintained for 15 or 120 min. In the third study, the intrathecal temperature was decreased to 27 degrees C for 2 h starting 5, 60, or 120 min after normothermic reperfusion. Animals survived for 2 or 3 days, at which time they were examined and perfusion fixed with 4% paraformaldehyde. RESULTS Normothermic ischemia followed by normothermic reflow resulted in spastic paraplegia and spinal neuronal degeneration. Immediate postischemic hypothermia (27 degrees C for 2 h) resulted in decreasing motor dysfunction. Incomplete protection was noted at 34 degrees C. Fifteen minutes of immediate cooling (27 degrees C) also provided significant protection. Delay of onset of post-reflow hypothermia (27 degrees C) by 5 min or more failed to provide protection. Histopathologic analysis revealed temperature-dependent suppression of spinal neurodegeneration, with no effect of delayed cooling. CONCLUSIONS These findings indicate that the immediate period of reperfusion (0-15 min) represents a critical period that ultimately defines the degree of spinal neuronal degeneration. Hypothermia, when initiated during this period, showed significant protection, with the highest efficacy observed at 27 degrees C.

Delayed Paraplegia After Spinal Cord Ischemic Injury Requires Caspase-3 Activation in Mice

Background and Purpose— Delayed paraplegia remains a devastating complication after ischemic spinal cord injury associated with aortic surgery and trauma. Although apoptosis has been implicated in the pathogenesis of delayed neurodegeneration, mechanisms responsible for the delayed paraplegia remain incompletely understood. The aim of this study was to elucidate the role of apoptosis in delayed motor neuron degeneration after spinal cord ischemia. Methods— Mice were subjected to spinal cord ischemia induced by occlusion of the aortic arch and left subclavian artery for 5 or 9 minutes. Motor function in the hind limb was evaluated up to 72 hours after spinal cord ischemia. Histological studies were performed to detect caspase-3 activation, glial activation, and motor neuron survival in the serial spinal cord sections. To investigate the impact of caspase-3 activation on spinal cord ischemia, outcome of the spinal cord ischemia was examined in mice deficient for caspase-3. Results— In wild-type mice, 9 minutes of spinal cord ischemia caused immediate paraplegia, whereas 5 minutes of ischemia caused delayed paraplegia. Delayed paraplegia after 5 minutes of spinal cord ischemia was associated with histological evidence of caspase-3 activation, reactive astrogliosis, microglial activation, and motor neuron loss starting at approximately 24 to 48 hours after spinal cord ischemia. Caspase-3 deficiency prevented delayed paraplegia and motor neuron loss after 5 minutes of spinal cord ischemia, but not immediate paraplegia after 9 minutes of ischemia. Conclusions— The present results suggest that caspase-3 activation is required for delayed paraplegia and motor neuron degeneration after spinal cord ischemia.

Interadductor approach to obturator nerve block for transurethral resection procedure: comparison with traditional approach

AbstractPurpose. We compared the interadductor approach of obturator nerve block with the traditional approach in terms of the insertion-adductor contraction interval (ICI), success rate, completion of the block, and plasma lidocaine concentration. Methods. An obturator nerve block by the interadductor approach was performed by needle insertion 1 cm behind the adductor longus tendon and 2 cm lateral to the pubic arch in 12 patients, and by the traditional approach in 12 patients. Results. The ICI with the interadductor approach was significantly shorter than that with the traditional approach. The success rate, completion of the block, and plasma lidocaine concentrations were similar with both approaches. Conclusion. The interadductor approach can provide faster identification of the obturator nerve than the traditional approach.

Influence of the Descending Thoracic Aortic Cross Clamping on Bispectral Index Value and Plasma Propofol Concentration in Humans

Background:In this study, the authors investigated changes in Bispectral Index (BIS) values and plasma propofol concentrations (Cp) after aortic cross clamping in the descending thoracic aortic aneurysm repair surgery during propofol anesthesia. Methods:Prospectively, in 10 patients undergoing thoracic aortic surgery during total intravenous anesthesia with propofol, BIS values were recorded during cross clamping of the descending thoracic aorta. In this study, the rate of propofol infusion was controlled to keep the BIS value between 30 and 60 throughout surgery. Simultaneously, Cp values in the blood samples taken from the right radial artery (area proximal to cross clamping) and the left femoral artery (area distal to cross clamping) were measured. Results:Approximately 15 min after initiating aortic cross clamping, BIS values in all cases started to decrease abruptly. Cp values of samples taken from the radial artery after cross clamping of the aorta were significantly (P < 0.05) increased compared with pre–cross clamp values (1.8 ± 0.4 &mgr;g/ml), and the mean Cp after aortic cross clamping varied between 3.0 and 5.3 &mgr;g/ml. In addition, there were significant differences in the Cp values between radial arterial and femoral arterial blood samples throughout aortic cross clamping. Cp values in samples from the radial artery were approximately two to seven times higher than those from the femoral artery. Conclusions:This study showed that Cp values increased and BIS values decreased rapidly after aortic cross clamping in thoracic aortic aneurysm repair surgery during propofol anesthesia. These findings suggested that all anesthesiologists should control the infusion rate carefully, taking the abrupt changes in its pharmacokinetics into consideration, especially during cross clamping of the descending thoracic aorta.

Intravenous Infusion of Dexmedetomidine Can Prevent the Degeneration of Spinal Ventral Neurons Induced by Intrathecal Morphine After a Noninjurious Interval of Spinal Cord Ischemia in Rats

BACKGROUND:In recent studies, we demonstrated that neuraxial morphine after noninjurious spinal cord ischemia in the rat could induce spastic paraplegia and degeneration of selective spinal ventral neurons. Our objective was to investigate the impact of dexmedetomidine infusion on the degeneration of spinal ventral neurons induced by intrathecal (IT) morphine after spinal cord ischemia. METHODS:Male Sprague-Dawley rats were given repetitive doses of IT morphine (40 &mgr;g × 2) at 1 and 5 h after a noninjurious interval (6 min) of spinal cord ischemia. The animals were assigned to one of the following four groups after the first IT injection (n = 8/group): Group S, IV infusion of saline (mL/h); Group Dex 0.1, dexmedetomidine (0.1 &mgr;g · kg−1 · h−1); Group Dex 1, dexmedetomidine (1 &mgr;g · kg−1 · h−1); Group Dex 3, dexmedetomidine (3 &mgr;g · kg−1 · h−1). Follow-up evaluation included a sedation scale, the Motor Deficit Index to determine neurological dysfunction and histopathology of the spinal cord at 72 h of reperfusion. RESULTS:IV dexmedetomidine produced a dose-dependent increase in the sedation index. Repetitive IT morphine injection induced paraplegia and degeneration of the spinal ventral neurons. IV dexmedetomidine at a sedative dose in comparison with saline significantly attenuated neurological dysfunction and histopathological consequences. CONCLUSION:These data show that repetitive administration of IT morphine can induce paraplegia with degeneration of spinal ventral neurons, which can be attenuated by IV dexmedetomidine at a sedative dose. The use of dexmedetomidine may provide beneficial effects on neurological outcome after IT morphine after spinal cord ischemia in rats.

The activation of spinal N-methyl-D-aspartate receptors may contribute to degeneration of spinal motor neurons induced by neuraxial morphine after a noninjurious interval of spinal cord ischemia.

We investigated the relationship between the degeneration of spinal motor neurons and activation of N-methyl-d-aspartate (NMDA) receptors after neuraxial morphine following a noninjurious interval of aortic occlusion in rats. Spinal cord ischemia was induced by aortic occlusion for 6 min with a balloon catheter. In a microdialysis study, 10 &mgr;L of saline (group C; n = 8) or 30 &mgr;g of morphine (group M; n = 8) was injected intrathecally (IT) 0.5 h after reflow, and 30 &mgr;g of morphine (group SM; n = 8) or 10 &mgr;L of saline (group SC; n = 8) was injected IT 0.5 h after sham operation. Microdialysis samples were collected preischemia, before IT injection, and at 2, 4, 8, 24, and 48 h of reperfusion (after IT injection). Second, we investigated the effect of IT MK-801 (30 &mgr;g) on the histopathologic changes in the spinal cord after morphine-induced spastic paraparesis. After IT morphine, the cerebrospinal fluid (CSF) glutamate concentration was increased in group M relative to both baseline and group C (P < 0.05). This increase persisted for 8 hrs. IT MK-801 significantly reduced the number of dark-stained α-motoneurons after morphine-induced spastic paraparesis compared with the saline group. These data indicate that IT morphine induces spastic paraparesis with a concomitant increase in CSF glutamate, which is involved in NMDA receptor activation. We suggest that opioids may be neurotoxic in the setting of spinal cord ischemia via NMDA receptor activation.

Emergence from propofol anesthesia in a nonagenarian at a Bispectral Index of 52.

In this case report, we describe a nonagenarian patient who could respond completely to verbal commands at a Bispectral Index (BIS) value of 52 after epidural lidocaine and IV propofol anesthesia. Measured blood lidocaine and propofol concentrations were 0.69 microg/mL and 0.74 microg/mL, respectively. Intraoperative awareness even in the recommended BIS range of 40-60 remains possible.