Multiple Cranial Nerve Blocks as an Alternative Preventative Therapy for Chronic Migraine.

OBJECTIVE: The objective of this prospective cohort study is to evaluate the efficacy of multiple cranial nerve blocks (MCNBs) as a preventative therapy for chronic migraine. BACKGROUND: MCNBs, namely greater occipital nerve (GON) blocks, are frequently used for the acute and transitional treatment of migraine. There is little evidence on the efficacy of repeated MCNBs as a preventative treatment for chronic migraine. DESIGN: This single-center, prospective cohort study collected demographic and outcome data on chronic migraine patients who had MCNBs in the headache service between June 2017 and March 2019. Outcome measures included reduction in headache days, Headache Impact Test 6 (HIT6) scores and patient-reported effectiveness of the blocks. RESULTS: Outcomes for 64 patients with a diagnosis of chronic migraine or chronic migraine with aura (MWA) were collected. Average age at first block procedure was 41 years (range 21-72) with a female predominance of 54/64 patients (84%). About 37/64 patients (58%) had repetitive occipital nerve blocks only, and 27/64 patients (42%) had occipital and trigeminal nerve blocks. Mean (±SD) reduction in headache days post-MCNBs was 5.4 (±5.0) days and mean (±SD) reduction in HIT6 scores was 5.3 (±10.3). About 42/64 patients (66%) responded to the MCNBs with at least a 30% reduction in headache days. Mean (±SD) duration of effect was 5.7 (±5.4) weeks. About 13/64 of the patients transformed to low-frequency episodic migraine on follow-up. About 22/64 patients (34%) showed no reduction in headache days or HIT6 scores. About 9/112 (8%) instances of minor post block complications were documented with a total of 501 injections. CONCLUSION: This study demonstrates that repetitive MCNBs could provide effective prevention in patients with chronic migraine.

Protective effect of magnesium sulfate on cranial nerves in preeclampsia rats through NF-κB/ICAM-1 pathway.

OBJECTIVE: The aim of this study was to investigate the protective effect of magnesium sulfate (MgSO4) on the cranial nerves of preeclampsia (PE) rats through the nuclear factor-κB (NF-κB)/intercellular adhesion molecule-1 (ICAM-1) pathway. MATERIALS AND METHODS: A total of 30 pregnant rats were randomly divided into three groups, including control group, model group, and treatment group, with 10 rats in each group. Systolic blood pressure was measured at 13 d, 15 d, and 19 d. The apoptosis level in brain tissues was detected via Western blotting and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Protein expression of genes was detected using immunohistochemical staining. Moreover, the messenger ribonucleic acid (mRNA) expressions of NF-κB and ICAM-1 in brain tissues were determined through Reverse Transcription-Polymerase Chain Reaction (RT-PCR). RESULTS: Systolic blood pressure exhibited significant differences among the three groups at 15 d and 19 d of gestational age (p<0.05). At 15 d of gestational age, systolic blood pressure was significantly higher in model group than that of control group (p<0.05). However, it was slightly lower in treatment group than model group (p<0.05). At 19 d of gestational age, systolic blood pressure was significantly higher in model group than control group (p<0.05). However, it decreased remarkably in treatment group when compared with model group (p<0.05). In treatment group, systolic blood pressure at 19 d was significantly lower than that at 15 d (p<0.05). Subsequent Western blotting revealed that the protein expression of B-cell lymphoma-2 (Bcl-2) in brain tissues decreased evidently, whereas the expression of Bcl-2 associated X protein (Bax) increased significantly in model group compared with control group, showing statistically significant differences (p<0.01). The protein expression of Bcl-2 in brain tissues increased significantly, while the expression of Bax declined remarkably in treatment group compared with model group (p<0.01). The number of apoptotic cells in model group and treatment group increased significantly compared with that in control group, with the largest in model group (p<0.05). However, it remarkably declined in treatment group compared with model group (p<0.05). These results suggested that MgSO4 treatment could significantly reduce neuronal apoptosis in PE rats. According to the results of immunohistochemistry, the protein expressions of NF-κB and ICAM-1 in brain tissues were significantly higher in model group and treatment group than those in control group (p<0.05). However, they were significantly lower in treatment group than model group (p<0.05). RT-PCR results manifested that the mRNA expressions of NF-κB and ICAM-1 in brain tissues exhibited evident differences among the three groups (p<0.05). Model group and treatment group showed significantly up-regulated mRNA expressions of NF-κB and ICAM-1 in brain tissues compared with control group (p<0.05). The highest mRNA expression was observed in model group. However, treatment group exhibited remarkably decreased mRNA expressions of NF-κB and ICAM-1 in brain tissues compared with model group (p<0.05). CONCLUSIONS: MgSO4 exerts a protective effect on cranial nerves of PE rats by inhibiting the NF-κB/ICAM-1 signaling pathway.

A Method for Cranial Nerve XI Silencing During Surgery of the Foramen Magnum Region: Technical Case Report.

BACKGROUND AND IMPORTANCE: Skull base surgery involves the microdissection and intraoperative monitoring of cranial nerves, including cranial nerve XI (CN XI). Manipulation of CN XI can evoke brisk trapezius contraction, which in turn may disturb the surgical procedure and risk patient safety. Here we describe a method for temporarily silencing CN XI via direct intraoperative application of 1% lidocaine. CLINICAL PRESENTATION: A 41-yr-old woman presented with symptoms of elevated intracranial pressure and obstructive hydrocephalus secondary to a hemangioblastoma of the right cerebellar tonsil. A far-lateral suboccipital craniotomy was performed for resection of the lesion. During the initial stages of microdissection, vigorous trapezius contraction compromised the course of the operation. Following exposure of the cranial and cervical portions of CN XI, lidocaine was applied to the course of the exposed nerve. Within 3 min, trapezius electromyography demonstrated neuromuscular silencing, and further manipulation of CN XI did not cause shoulder movements. Approximately 30 min after lidocaine application, trapezius contractions returned, and lidocaine was again applied to re-silence CN XI. Gross total resection of the hemangioblastoma was performed during periods of CN XI inactivation, when trapezius contractions were absent. CONCLUSION: Direct application of lidocaine to CN XI temporarily silenced neuromuscular activity and prevented unwanted trapezius contraction during skull base microsurgery. This method improved operative safety and efficiency by significantly reducing patient movement due to the unavoidable manipulation of CN XI.

CXCL12 has therapeutic value in facial nerve injury and promotes Schwann cells autophagy and migration via PI3K-AKT-mTOR signal pathway.

Facial nerve injury is a clinically common disease accompanied by demyelination of damaged nerves. The remyelination of damaged nerves and the unsatisfactory function recovery are problems that have been plaguing people for a long time. The role that CXCL12 plays after facial nerve injury remains unknown. Our experiments found that the expression of CXCL12 was up-regulated in the early stage of facial nerve injury and decreased after two weeks. Further research found that CXCL12 had no effect on Schwann cells proliferation, apoptosis and cell cycle, while significantly promoted Schwann cells migration. Treatment with CXCL12 decreased the phosphorylation of PI3K, AKT and mTOR, but increased autophagy marker LC3II/I. The CXCL12-induced Schwann cells migration was significantly attenuated by inhibition of autophagy and activation of PI3K pathway through pretreatment with 3-MA and IGF-1 respectively, and this effect was enhanced by PI3K pathway inhibitor LY294002. Animal experiment also confirmed that CXCL12 could improve facial nerve function and myelin regeneration. The findings of this study indicate that CXCL12 can promote the migration of Schwann cells and potentially become a key molecule in the repair of facial nerve injury.

A novel technique to identify the nerve of origin in head and neck schwannomas.

OBJECTIVE: Identifying the nerve of origin in head and neck schwannomas is a diagnostic challenge. Surgical management leads to a risk of permanent deficit. Accurate identification of the nerve would improve operative planning and patient counselling. METHODS: Three patients with head and neck schwannomas underwent a diagnostic procedure hypothesised to identify the nerve of origin. The masses were infiltrated with 1 per cent lidocaine solution, and the patients were observed for neurological deficits. RESULTS: All three patients experienced temporary loss of nerve function after lidocaine injection. Facial nerve palsy, voice changes with documented unilateral same-side vocal fold paralysis, and numbness in the distribution of the maxillary nerve (V2), respectively, led to a likely identification of the nerve of origin. CONCLUSION: Injection of lidocaine into a schwannoma is a safe, in-office procedure that produces a temporary nerve deficit, which may enable accurate identification of the nerve of origin of a schwannoma. Identifying the nerve of origin enhances operative planning and patient counselling.

Acute Trigeminal Neuralgia Associated with Initiation of Emtricitabine/Tenofovir for HIV Pre-Exposure Prophylaxis.

HIV pre-exposure prophylaxis (PrEP) with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) fixed-dose combination (FTC/TDF) is undergoing rapid scale-up in the United States. While FTC/TDF is typically well tolerated, to our knowledge, cranial nerve pathology associated with FTC/TDF has not been previously described. We report the case of a 35-year-old patient who began FTC/TDF PrEP and developed acute trigeminal neuralgia. The neurologic symptoms resolved after treatment discontinuation and recurred upon rechallenge, resulting in permanent discontinuation of PrEP treatment.

Neuroprotective effect of lurasidone via antagonist activities on histamine in a rat model of cranial nerve involvement.

Cranial nerve involvement frequently involves neuron damage and often leads to psychiatric disorder caused by multiple inducements. Lurasidone is a novel antipsychotic agent approved for the treatment of cranial nerve involvement and a number of mental health conditions in several countries. In the present study, the neuroprotective effect of lurasidone by antagonist activities on histamine was investigated in a rat model of cranial nerve involvement. The antagonist activities of lurasidone on serotonin 5­HT7, serotonin 5­HT2A, serotonin 5­HT1A and serotonin 5­HT6 were analyzed, and the preclinical therapeutic effects of lurasidone were examined in a rat model of cranial nerve involvement. The safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lurasidone were also assessed in the cranial nerve involvement model. The therapeutic dose of lurasidone was 0.32 mg once daily, administered continuously in 14­day cycles. The results of the present study found that the preclinical prescriptions induced positive behavioral responses following treatment with lurasidone. The MTD was identified as a once daily administration of 0.32 mg lurasidone. Long­term treatment with lurasidone for cranial nerve involvement was shown to improve the therapeutic effects and reduce anxiety in the experimental rats. In addition, treatment with lurasidone did not affect body weight. The expression of the language competence protein, Forkhead­BOX P2, was increased, and the levels of neuroprotective SxIP motif and microtubule end­binding protein were increased in the hippocampal cells of rats with cranial nerve involvement treated with lurasidone. Lurasidone therapy reinforced memory capability and decreased anxiety. Taken together, lurasidone treatment appeared to protect against language disturbances associated with negative and cognitive impairment in the rat model of cranial nerve involvement, providing a basis for its use in the clinical treatment of patients with cranial nerve involvement.

Supratrochlear Neuralgia: A Prospective Case Series of 15 Patients.

OBJECTIVE: The aim of this study was to describe clinical features unique to supratrochlear neuralgia. BACKGROUND: The supratrochlear nerve supplies the medial aspect of the forehead. Due to the intricate relationship between supraorbital and supratrochlear nerves, neuralgic pain in this region has been traditionally attributed to supraorbital neuralgia. No cases of supratrochlear neuralgia have been reported so far. METHODS: From 2009 through 2016, we prospectively recruited patients with pain confined to the territory of the supratrochlear nerve. RESULTS: Fifteen patients (13 women, 2 men; mean age 51.4 years, standard deviation 14.9) presented with pain in the lower paramedian forehead, extending to the eyebrow in two patients and to the internal angle of the orbit in another. Pain was unilateral in 11 patients (six on the right, five on the left), and bilateral in four. Six patients had continuous pain and nine described intermittent pain. Palpation of the supratrochlear nerve at the medial third of the supraorbital rim resulted in hypersensitivity in all cases. All but one patient exhibited sensory disturbances within the painful area. Fourteen patients underwent anesthetic blockades of the supratrochlear nerve, with immediate relief in all cases and long-term remission in three. Six of them had received unsuccessful anesthetic blocks of the supraorbital nerve. Five patients were treated successfully with oral drugs and one patient was treated with radiofrequency. CONCLUSIONS: Supratrochlear neuralgia is an uncommon disorder causing pain in the medial region of the forehead. It may be differentiated from supraorbital neuralgia and other similar headaches and neuralgias based on the topography of the pain and the response to anesthetic blockade.

Characterization of Neurologic and Ophthalmologic Safety of Oral Administration of Tedizolid for Up to 21 Days in Healthy Volunteers.

BACKGROUND: Antibacterials that inhibit protein synthesis may be associated with mitochondrial toxicity, manifested as serious optic or peripheral neuropathy or myelosuppression. Tedizolid is a novel oxazolidinone antibacterial that may have reduced the potential for mitochondrial toxicity. STUDY QUESTION: Based on the results of 2 studies (NCT01623401 and NCT00671814) conducted early in the tedizolid development program, what is the potential for drug-induced optic and peripheral neuropathies with tedizolid treatment? METHODS: Two phase-1 studies were conducted in healthy volunteers. The first was an open-label study in which subjects received 200 mg of oral tedizolid phosphate once daily for 10 days. The second was a double-blind, placebo- and active-controlled, dose-escalating (multiple-administration) study in which subjects received 200, 300, or 400 mg of oral tedizolid phosphate once daily or 600 mg of oral linezolid twice daily or oral placebo for 21 days. Overall safety and tolerability were assessed, and extensive ophthalmologic and neurologic assessments were performed in both studies. RESULTS: In these 2 studies in healthy subjects, tedizolid administered for up to 21 days was not associated with drug-related ophthalmologic or neurologic adverse events. Incidences of adverse events involving the eye or the nervous system were generally low, and no clinically meaningful changes in ophthalmologic or neurologic test results were recorded during either study. CONCLUSIONS: Using an extensive battery of ophthalmologic tests and detailed neurologic clinical examination, there was no evidence of clinical or subclinical neurologic or ophthalmologic changes suggestive of peripheral or optic neuropathy in healthy volunteers who received therapeutic and supratherapeutic doses of oral tedizolid for periods of up to 21 days.

Sensory-motor axonal polyneuropathy involving cranial nerves: An uncommon manifestation of disulfiram toxicity.

Disulfiram (tetraethylthiuram disulfide) has been used for the treatment of alcohol dependence. An axonal sensory-motor polyneuropathy with involvement of cranial pairs due to disulfiram is exceedingly rare. The authors report a unique case of an extremely severe axonal polyneuropathy involving cranial nerves that developed within weeks after a regular dosage of 500mg/day disulfiram. To the authors best knowledge, such a severe and rapidly-progressive course has never been described with disulfiram dosages of only 500mg/day.

Influence of general anaesthesia on the brainstem. / Influencia de la anestesia general sobre el tronco encefálico.

The exact role of the brainstem in the control of body functions is not yet well known and the same applies to the influence of general anaesthesia on brainstem functions. Nevertheless in all general anaesthesia the anaesthesiologist should be aware of the interaction of anaesthetic drugs and brainstem function in relation to whole body homeostasis. As a result of this interaction there will be changes in consciousness, protective reflexes, breathing pattern, heart rate, temperature or arterial blood pressure to name a few. Brainstem function can be explored using three different approaches: clinically, analyzing changes in brain electric activity or using neuroimaging techniques. With the aim of providing the clinician anaesthesiologist with a global view of the interaction between the anaesthetic state and homeostatic changes related to brainstem function, the present review article addresses the influence of anaesthetic drug effects on brainstem function through clinical exploration of cranial nerves and reflexes, analysis of electric signals such as electroencephalographic changes and what it is known about brainstem through the use of imaging techniques, more specifically functional magnetic resonance imaging.

Delayed onset and long-lasting hemidiaphragmatic paralysis and cranial nerve deficit after interscalene nerve block for rotator cuff repair in beach chair position.

Hemidiaphragmatic paralysis is the most common adverse effect associated with interscalene block. In most cases, it resolves with the resolution of nerve blockade with only an estimated incidence of 0.048% persisting for longer duration. Occasionally, interscalene block is also associated with recurrent laryngeal nerve block and seldom with cranial nerve paresis. We present a case of delayed onset and prolonged hemidiaphragmatic paralysis that was associated with 3 cranial nerve deficits after interscalene nerve block for shoulder surgery performed under general anesthesia in the beach chair position. Etiology is unclear, but most likely multifactorial.

[The protective effect of alpha-2 adrenergic agonist on cranial nerve in rats with brain injury].

OBJECTIVE: To investigate the neuroprotective effect of α2 adrenergic agonist, dexmedetomidine on tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) in brain tissue and serum S-100ß protein level in traumatic brain injury rats. METHODS: Seventy-two male Sprague-Dawley rats were randomly divided into sham operation group (group S), traumatic brain injury group (group C), and dexmedetomidine group (group D), 24 rats in each group; each of which was divided into 6, 12, 24 and 48 hours subgroup, 6 rats in each subgroup. Parietal brain contusion was produced by reformed Feeney method. The group S underwent sham operation without blunt force stroke; group D underwent blunt force stroke, then received loading dose of dexmedetomidine, 3 µg/kg with common jugular vein injection and continued infusion with 3 µg·kg(-1)·h(-1) for 2 hours. The total dosage of dexmedetomidine was 9 µg/kg with a volume of 4 ml; group C underwent 0.9% NaCl, 4 ml injection at the same time point with the same method. The S-100 protein activity in arteria cruralis serum was detected at the each time point by ELISA and TNF-α, IL-6 in the brain tissue were detected by ELISA. RESULTS: There were no significant difference of TNF-α activity among time point of 6, 12, 24 and 48 h in group S ((2.07±0.06), (2.01±0.03), (2.11±0.05), and (2.08±0.04) pg/mg, F=1.147, P>0.05), no significant difference of IL-6 activity among the same time point ((4.03±0.06), (4.07±0.09), (4.06±0.04), and (4.55±0.09) pg/mg, F=1.176, P>0.05), and no significant difference of serum S-100ß activity among the same time too ((0.37±0.07), (0.36±0.02), (0.35±0.06), and (0.39±0.11) µg/L, F=1.045, P>0.05). The above indexes in group C were higher than those in group S, and the above indexes in group D were higher than those in group S and lower than those in group C (all P<0.05). CONCLUSION: Alpha-2 adrenergic agonist, dexmedetomidine could dramatically inhibit inflammatory reaction induced by traumatic brain injury in rats and protect brain tissue.

Complement component C3 and butyrylcholinesterase activity are associated with neurodegeneration and clinical disability in multiple sclerosis.

Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear. In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects. We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18). C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL. C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease. BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples. In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability. Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation. These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

External QX-314 inhibits evoked cranial primary afferent synaptic transmission independent of TRPV1.

The cell-impermeant lidocaine derivative QX-314 blocks sodium channels via intracellular mechanisms. In somatosensory nociceptive neurons, open transient receptor potential vanilloid type 1 (TRPV1) receptors provide a transmembrane passageway for QX-314 to produce long-lasting analgesia. Many cranial primary afferents express TRPV1 at synapses on neurons in the nucleus of the solitary tract and caudal trigeminal nucleus (Vc). Here, we investigated whether QX-314 interrupts neurotransmission from primary afferents in rat brain-stem slices. Shocks to the solitary tract (ST) activated highly synchronous evoked excitatory postsynaptic currents (ST-EPSCs). Application of 300 µM QX-314 increased the ST-EPSC latency from TRPV1+ ST afferents, but, surprisingly, it had similar actions at TRPV1- ST afferents. Continued exposure to QX-314 blocked evoked ST-EPSCs at both afferent types. Neither the time to onset of latency changes nor the time to ST-EPSC failure differed between responses for TRPV1+ and TRPV1- inputs. Likewise, the TRPV1 antagonist capsazepine failed to prevent the actions of QX-314. Whereas QX-314 blocked ST-evoked release, the frequency and amplitude of spontaneous EPSCs remained unaltered. In neurons exposed to QX-314, intracellular current injection evoked action potentials suggesting a presynaptic site of action. QX-314 acted similarly at Vc neurons to increase latency and block EPSCs evoked from trigeminal tract afferents. Our results demonstrate that QX-314 blocked nerve conduction in cranial primary afferents without interrupting the glutamate release mechanism or generation of postsynaptic action potentials. The TRPV1 independence suggests that QX-314 either acted extracellularly or more likely entered these axons through an undetermined pathway common to all cranial primary afferents.

Motor palsies of cranial nerves (excluding VII) after vaccination: reports to the US Vaccine Adverse Event Reporting System.

We reviewed cranial nerve palsies, other than VII, that have been reported to the US Vaccine Adverse Event Reporting System (VAERS). We examined patterns for differences in vaccine types, seriousness, age, and clinical characteristics. We identified 68 reports of cranial nerve palsies, most commonly involving the oculomotor (III), trochlear (IV), and abducens (VI) nerves. Isolated cranial nerve palsies, as well as palsies occurring as part of a broader clinical entity, were reported. Forty reports (59%) were classified as serious, suggesting that a cranial nerve palsy may sometimes be the harbinger of a broader and more ominous clinical entity, such as a stroke or encephalomyelitis. There was no conspicuous clustering of live vs. inactivated vaccines. The patient age range spanned the spectrum from infants to the elderly. Independent data may help to clarify whether, when, and to what extent the rates of cranial nerve palsies following particular vaccines may exceed background levels.

Effects of mycophenolic acid alone and in combination with its metabolite mycophenolic acid glucuronide on rat embryos in vitro.

Mycophenolic acid (MPA) is an immunosuppressive agent that acts as a selective, non-reversible inhibitor of the enzyme inosine-5'-monophosphate dehydrogenase (IMPDH). Malformations have been described in children after maternal exposure to mycophenolate. However, the causal link is unclear in most cases because women had been treated with a combination of drugs and birth defects may have other causes. Therefore, it is important to study the action of this drug and its main metabolite on embryonic tissue. We studied the teratogenic potential of MPA and its major metabolite, the mycophenolic acid glucuronide (MPAG) in the rat whole-embryo culture. A total of 147 day 9.5 embryos were cultivated for 48 h in the standard medium containing 85 % serum. We tested MPA at concentrations of 0.1; 0.25; 0.5; 0.75 mg/l (0.31; 0.78; 1.56; 2.34 µM) and MPA glucuronide at concentrations of 3; 10; 30; 100 mg/l (6.04; 20.14; 60.43; 201.43 µM). Both substances are highly protein bound, and MPA glucuronide might displace MPA from protein binding. Therefore, we examined whether the effects of MPA can be enhanced when studied in combination with the glucuronide. Furthermore, the focus was on additional endpoints to the standard evaluation of cultivated embryos, such as development of cranial nerves [trigeminal nerve (V), facial nerve (VII), glossopharyngeal nerve (IX), vagus nerve (X)] after staining with an antibody against 2H3 neurofilament. Ultrastructural changes were evaluated by electron microscopy. At a concentration of 0.75 mg MPA/l medium, all embryos showed dysmorphic changes. Embryos exposed to 0.25 mg MPA/l medium showed impaired development of nerves, and at 0.1 mg/l, no effects were detectable. Concentration-dependent ultrastructural changes, such as signs of apoptosis, were found by electron microscopy. The examination of the metabolite in this assay showed that at a concentration of 100 mg MPAG/l, the embryos exhibited distinct malformations. This is probably caused by MPA, which was detectable at 0.6 % in the material used for our experiments. The combination of the parent compound (0.03; 0.1; 0.25 mg/l) with its metabolite MPAG (3 mg/l) did not cause enhanced toxicity under our experimental conditions. IMPDH, the target enzyme of MPA, could be detected in rat embryos on day 9.5 of embryonic development as well as at the end of the culture period 48 h later. In summary, MPA impairs embryonic development at low, therapeutically relevant concentrations, but the glucuronide does not exhibit such a potential. Activity of MPA is not enhanced by MPAG.

Activated cranial cervical cord neurons affect left ventricular infarct size and the potential for sudden cardiac death.

To evaluate whether cervical spinal neurons can influence cardiac indices and myocyte viability in the acutely ischemic heart, the hearts of anesthetized rabbits subjected to 30 min of LAD coronary arterial occlusion (CAO) were studied 3h after reperfusion. Control animals were compared to those exposed to pre-emptive high cervical cord stimulation (SCS; the dorsal aspect of the C1-C2 spinal cord was stimulated electrically at 50 Hz; 0.2 ms; 90% of motor threshold, starting 15 min prior to and continuing throughout CAO). Four groups of animals were so tested: 1) neuroaxis intact; 2) prior cervical vagotomy; 3) prior transection of the dorsal spinal columns at C6; and 4) following pharmacological treatment [muscarinic (atropine) or adrenergic (atenolol, prazosin or yohimbine) receptor blockade]. Infarct size (IS) was measured by tetrazolium, expressed as percentage of risk zone. C1-C2 SCS reduced acute ischemia induced IS by 43%, without changing the incidence of sudden cardiac death (SCD). While SCS-induced reduction in IS was unaffected by vagotomy, it was no longer evident following transection of C6 dorsal columns or atropinization. Beta-adrenoceptor blockade eliminated ischemia induced SCD, while alpha-receptor blockade doubled its incidence. During SCS, myocardial ischemia induced SCD was eliminated following vagotomy while remaining unaffected by atropinization. These data indicate that, in contrast to thoracic spinal neurons, i) cranial cervical spinal neurons affect both adrenergic and cholinergic motor outflows to the heart such that ii) their activation modifies ventricular infarct size and lethal arrhythmogenesis.