Muscle membrane properties in A pig sepsis model: Effect of norepinephrine.

INTRODUCTION: Sepsis-induced myopathy and critical illness myopathy are common causes of muscle weakness in intensive care patients. This study investigated the effect of different mean arterial blood pressure (MAP) levels on muscle membrane properties following experimental sepsis. METHODS: Sepsis was induced with fecal peritonitis in 12 of 18 anesthetized and mechanically ventilated pigs. Seven were treated with a high (75-85 mmHg) and 5 were treated with a low (≥60 mmHg) MAP target for resuscitation. In septic animals, resuscitation was started 12 h after peritonitis induction, and muscle velocity recovery cycles were recorded 30 h later. RESULTS: Muscles in the sepsis/high MAP group showed an increased relative refractory period and reduced early supernormality compared with the remaining septic animals and the control group, indicating membrane depolarization and/or sodium channel inactivation. The membrane abnormalities correlated positively with norepinephrine dose. DISCUSSION: Norepinephrine may contribute to sepsis-induced abnormalities in muscle by impairing microcirculation. Muscle Nerve 57: 808-813, 2018.

Muscle velocity recovery cycles: Comparison between surface and needle recordings.

INTRODUCTION: Recording of muscle velocity recovery cycles (MVRCs) has been developed as a technique to investigate the pathophysiology of muscle diseases. MVRCs have been measured by direct muscle stimulation and concentric electromyographic needle recording. This study was undertaken to determine whether recordings can be made with surface electrodes. METHODS: MVRCs with 1 and 2 conditioning stimuli were recorded simultaneously with concentric needle and surface electrodes from the brachioradialis muscle in 12 healthy volunteers. Muscle relative refractory period, early and late supernormality, and extra-late supernormality were compared between the recording techniques. RESULTS: Surface recordings were possible in all subjects. The multifiber action potentials recorded with surface electrodes were smaller than those recorded with needles, but there was no significant difference between any of their MVRC properties. CONCLUSIONS: MVRCs can be recorded with surface electrodes in healthy subjects. The use of surface electrodes may facilitate the technique of recording MVRCs.

In vivo assessment of muscle membrane properties in myotonic dystrophy.

INTRODUCTION: Myotonia in myotonic dystrophy types 1 (DM1) and 2 (DM2) is generally attributed to reduced chloride-channel conductance. We used muscle velocity recovery cycles (MVRCs) to investigate muscle membrane properties in DM1 and DM2, using comparisons with myotonia congenita (MC). METHODS: MVRCs and responses to repetitive stimulation were compared between patients with DM1 (n = 18), DM2 (n = 5), MC (n = 18), and normal controls (n = 20). RESULTS: Both DM1 and DM2 showed enhanced late supernormality after multiple conditioning stimuli, indicating delayed repolarization as in MC. Contrary to MC, however, DM1 showed reduced early supernormality after multiple conditioning stimuli, and weak DM1 patients also showed abnormally slow latency recovery after repetitive stimulation. CONCLUSIONS: These findings support the presence of impaired chloride conductance in both DM1 and DM2. The early supernormality changes indicate that sodium currents were reduced in DM1, whereas the weakness-associated slow recovery after repetitive stimulation may provide an indication of reduced Na(+) /K(+) -ATPase activation. Muscle Nerve 54: 249-257, 2016.

Arginine butyrate per os protects mdx mice against cardiomyopathy, kyphosis and changes in axonal excitability.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by lack of dystrophin, a sub-sarcolemmal protein, which leads to dramatic muscle deterioration. We studied in mdx mice, the effects of oral administration of arginine butyrate (AB), a compound currently used for the treatment of sickle cell anemia in children, on cardiomyopathy, vertebral column deformation and electromyographic abnormalities. Monthly follow-up by echocardiography from the 8th month to the 14th month showed that AB treatment protected the mdx mice against drastic reduction (20-23%) of ejection fraction and fractional shortening, and also against the ≈20% ventricular dilatation and 25% cardiac hypertrophy observed in saline-treated mdx mice. The phenotypic improvement was corroborated by the decrease in serum CK level and by better fatigue resistance. Moreover, AB treatment protected against the progressive spinal deformity observed in mdx mice, another similarity with DMD patients. The value of the kyphosis index in AB-treated mice reached 94% of the value in C57BL/10 mice. Finally, axonal excitability parameters such as the membrane resting potential, the threshold and amplitude of the action potential, the absolute and relative refractory periods and the supernormal and subnormal periods, recorded from caudal and plantar muscles in response to excitability tests, that were modified in saline-treated mdx mice were not significantly changed, compared with wild-type animals, in AB-treated mdx mice. All of these results suggest that AB could be a potential treatment for DMD patients.

Chloride channels in myotonia congenita assessed by velocity recovery cycles.

INTRODUCTION: Myotonia congenita (MC) is caused by congenital defects in the muscle chloride channel CLC-1. This study used muscle velocity recovery cycles (MVRCs) to investigate how membrane function is affected. METHODS: MVRCs and responses to repetitive stimulation were compared between 18 patients with genetically confirmed MC (13 recessive, 7 dominant) and 30 age-matched, normal controls. RESULTS: MC patients exhibited increased early supernormality, but this was prevented by treatment with sodium channel blockers. After multiple conditioning stimuli, late supernormality was enhanced in all MC patients, indicating delayed repolarization. These abnormalities were similar between the MC subtypes, but recessive patients showed a greater drop in amplitude during repetitive stimulation. CONCLUSIONS: MVRCs indicate that chloride conductance only becomes important when muscle fibers are depolarized. The differential responses to repetitive stimulation suggest that, in dominant MC, the affected chloride channels are activated by strong depolarization, consistent with a positive shift of the CLC-1 activation curve.

A mouse model of Schwartz-Jampel syndrome reveals myelinating Schwann cell dysfunction with persistent axonal depolarization in vitro and distal peripheral nerve hyperexcitability when perlecan is lacking.

Congenital peripheral nerve hyperexcitability (PNH) is usually associated with impaired function of voltage-gated K(+) channels (VGKCs) in neuromyotonia and demyelination in peripheral neuropathies. Schwartz-Jampel syndrome (SJS) is a form of PNH that is due to hypomorphic mutations of perlecan, the major proteoglycan of basement membranes. Schwann cell basement membrane and its cell receptors are critical for the myelination and organization of the nodes of Ranvier. We therefore studied a mouse model of SJS to determine whether a role for perlecan in these functions could account for PNH when perlecan is lacking. We revealed a role for perlecan in the longitudinal elongation and organization of myelinating Schwann cells because perlecan-deficient mice had shorter internodes, more numerous Schmidt-Lanterman incisures, and increased amounts of internodal fast VGKCs. Perlecan-deficient mice did not display demyelination events along the nerve trunk but developed dysmyelination of the preterminal segment associated with denervation processes at the neuromuscular junction. Investigating the excitability properties of the peripheral nerve suggested a persistent axonal depolarization during nerve firing in vitro, most likely due to defective K(+) homeostasis, and excluded the nerve trunk as the original site for PNH. Altogether, our data shed light on perlecan function by revealing critical roles in Schwann cell physiology and suggest that PNH in SJS originates distally from synergistic actions of peripheral nerve and neuromuscular junction changes.

Muscle velocity recovery cycles: effects of repetitive stimulation on two muscles.

INTRODUCTION: We sought to characterize the excitability properties of tibialis anterior (TA) and brachioradialis (BR) muscles at rest and during electrically induced muscle activation in normal subjects. METHODS: Two centers recruited 10 subjects each. Multi-fiber velocity recovery cycles (VRCs) were recorded from TA (both centers) and BR (one center). VRCs were assessed at rest and during repetitive stimulation (intermittent 20 Hz for 6 min). Changes in latency and peak amplitude of the muscle action potential induced by a frequency ramp to 30 Hz were also characterized. RESULTS: Excitability properties recorded from TA were very similar between centers. Repetitive stimulation generated marked excitability changes, which were similar between TA and BR. CONCLUSIONS: Standardized tests of muscle VRCs and responses to repetitive stimulation can provide consistent measures of membrane function and may encourage their wider use in clinical neurophysiology to investigate the pathophysiology of neuromuscular disorders.

Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles.

INTRODUCTION: Andersen-Tawil syndrome (ATS) due to Kir2.1mutations typically manifests as periodic paralysis, cardiac arrhythmias and developmental abnormalities but is often difficult to diagnose clinically. This study was undertaken to determine whether sarcolemmal dysfunction could be identified with muscle velocity recovery cycles (MVRCs). METHODS: Eleven genetically confirmed ATS patients and 20 normal controls were studied. MVRCs were recorded with 1, 2, and 5 conditioning stimuli and with single conditioning stimuli during intermittent repetitive stimulation at 20 Hz, in addition to the long exercise test. RESULTS: ATS patients had longer relative refractory periods (P < 0.0001) and less early supernormality, consistent with membrane depolarization. Patients had reduced enhancement of late supernormality with 5 conditioning stimuli (P < 0.0001), and less latency reduction during repetitive stimulation (P < 0.001). Patients were separated completely from controls by combining MVRC and repetitive stimulation. CONCLUSIONS: MVRCs combined with repetitive stimulation differentiated ATS patients from controls more effectively than the conventional long-exercise test.

A model of mouse motor nerve excitability and the effects of polarizing currents.

This study was undertaken to develop a theoretical model of mouse motor nerve excitability, and to validate it by application to recordings from mouse axons with membrane potential altered by polarizing currents. Multiple excitability tests were performed on the caudal motor nerves of 12 mice. Membrane potential was artificially modified by injecting polarizing currents through the stimulating electrodes (±20% of threshold for 1 ms pulse). A human motor nerve model was adapted to the unpolarized mouse recordings by adjusting membrane parameters to optimize the fit. To evaluate the usefulness of the model, we then determined the parameter changes which best fitted the recordings from depolarized and hyperpolarized tail nerves. The recordings from the normal axons were well fitted by a model in which axons were hyperpolarized by 4 mV, and nodal sodium and slow potassium conductances were reduced by half, compared with human median nerve motor axons. The changes with polarizing currents were qualitatively similar to those in human axons, and modeling correctly identified a change in current as the best-fitting explanation for the altered excitability. We conclude that this new model should help identify changes in membrane potential and probably in other membrane parameters in mouse models of neurological disease.

Excitability properties of mouse motor axons in the mutant SOD1(G93A) model of amyotrophic lateral sclerosis.

Non-invasive excitability studies of motor axons in patients with amyotrophic lateral sclerosis (ALS) have revealed a changing pattern of abnormal membrane properties with disease progression, but the heterogeneity of the changes has made it difficult to relate them to pathophysiology. The SOD1(G93A) mouse model of ALS displays more synchronous motoneuron pathology. Multiple excitability measures of caudal and sciatic nerves in mutant and wild-type mice were compared before onset of signs and during disease progression (4-19 weeks), and they were related to changes in muscle fiber histochemistry. Excitability differences indicated a modest membrane depolarization in SOD1(G93A) axons at about the time of symptom onset (8 weeks), possibly due to deficient energy supply. Previously described excitability changes in ALS patients, suggesting altered sodium and potassium conductances, were not seen in the mice. This suggests that those changes relate to features of the human disease that are not well represented in the animal model.

Excitability properties of motor axons in the maturing mouse.

Non-invasive excitability tests have been developed to appraise axonal membrane properties in peripheral nerves and are contributing to our understanding of neuropathies and neuronopathies. These techniques have been adapted to in vivo and in vitro rat models, but little data are available on mice, although mice provide more transgenic models of neurological disorders. This study was therefore undertaken to assess the suitability of mice to model human nerve excitability measurements and to document changes during maturation. Female mice, aged 4-19 weeks, were recorded under isoflurane anesthesia. Electrical stimuli were applied via surface electrodes to the caudal motor nerve and compound muscle action potentials (CMAPs) recorded from the tail with needle electrodes. Then, the sciatic nerve was stimulated above the ankle and CMAPs recorded from plantar muscles. The method was only minimally invasive, enabling the same animal to be tested up to eight times at weekly intervals. As in human studies, the multiple excitability program recorded stimulus-response, strength-duration, and current-threshold relationships; threshold electrotonus; and recovery cycle. The response waveforms were qualitatively similar to those from human axons. This resemblance was closer for the caudal nerve, which also showed more marked changes with age. Early hyperpolarizing electrotonus fell sharply from weeks 4 to 13 (p < 0.0001), while a progressive increase in superexcitability occurred throughout the period studied (p < 0.001). We conclude that multiple measures of nerve excitability can be performed reliably in mice in vivo, preferentially on the tail, and are suitable for longitudinal studies, but age matching is critical for younger animals.

Alteration of motor nerve recovery cycle in multiple sclerosis.

OBJECTIVE: To study peripheral motor nerve excitability in patients with multiple sclerosis (MS). METHODS: Twenty MS patients with normal nerve conduction parameters and no predisposing factors for peripheral neuropathy were included. Compound muscle action potentials were recorded from the abductor digiti minimi muscle to paired-pulse stimulation of the ulnar nerve at the wrist, with various interstimuli intervals (ISIs) ranging from 1 to 7 ms. The motor nerve recovery cycle was studied using a subtraction method. We measured the durations of the absolute and relative refractory periods (ARP, RRP) and the percentages of refractoriness and supernormality at 2.6 and 7 ms ISIs. The results obtained in MS patients were compared to normative values established in 20 age-matched healthy subjects. Correlations were made between excitability parameters and MS type (relapsing-remitting or progressive), EDSS score, disease duration, and motor evoked potential (MEP) abnormalities. RESULTS: Supernormality was extremely reduced, refractoriness was increased and both ARP and RRP were prolonged in MS patients vs. healthy controls. These alterations did not correlate to clinical features or to the presence of MEP abnormalities. CONCLUSIONS: Changes in motor nerve recovery cycle revealed the existence of subtle impairment in the peripheral nervous system of MS patients, mainly characterized by a reduced supernormality. SIGNIFICANCE: Peripheral nerve excitability alterations in MS may be due to axoglial paranodal dysjunction or juxtaparanodal dysfunction.

Neuromuscular excitability properties in myotonic dystrophy type 1.

OBJECTIVE: To study neuromuscular excitability in patients with dystrophia myotonica type 1 (DM1). METHODS: The neuromuscular recovery cycle following motor nerve stimulation was assessed in 16 DM1 patients who had no sign of peripheral neuropathy or diabetes. Compound muscle action potentials were recorded from the adductor digiti minimi muscle to ulnar nerve stimulation at the wrist. Paired pulses were delivered, consisting of a conditioning stimulus of supramaximal intensity, followed by a submaximal test stimulus. Interstimuli intervals (ISIs) ranged between 1 and 8ms. Durations of the absolute and relative refractory periods (ARP, RRP) and percentages of refractoriness and supernormality at ISIs of 2.6 and 7ms, respectively, were computed using a subtraction method. The results obtained in the series of DM1 patients were compared to those obtained in six patients with other forms of myotonia and to normative values established in a series of age-matched healthy subjects. Correlations were made between excitability parameters, the number of cytosine-thymine-guanine (CTG) repeats, and the severity of myotonia, scored clinically. RESULTS: Compared to controls, DM1 patients presented prolonged durations of ARP and RRP, increased refractoriness and reduced supernormality. The decrease in refractoriness correlated with both the number of CTG repeats and the severity of myotonia. CONCLUSIONS: Changes in the recovery cycle following supramaximal motor nerve stimulation revealed the existence of subtle alterations of neuromuscular excitability in DM1 patients. SIGNIFICANCE: Increase in refractoriness together with a reduced supernormality was consistent with a process of membrane depolarization. Such a depolarization may be related to the loss of chloride channels or to alterations in sodium conductance in the motor axon or the muscle fiber.

A reappraisal of various methods for measuring motor nerve refractory period in humans.

OBJECTIVE: To compare various techniques of stimulation and methods of analysis to estimate absolute (ARP) and relative (RRP) refractory periods in motor nerve trunks of humans. METHODS: Double collision (DC) technique and two types of paired pulse (PP) technique, with test stimulation of supramaximal (PP(supra)) or submaximal (PP(sub)) intensity, were applied to 32 healthy subjects. The ulnar nerve was stimulated either at a single site (wrist) for the PP techniques or at two sites (wrist and elbow) for the DC technique, with various distal interstimuli intervals (ISIs). The elicited compound muscle action potentials (CMAPs) were recorded from the abductor digitorum minimi muscle. The DC technique provided estimates of minimal and maximal ARPs, whereas maximal RRP values were obtained with the PP techniques. Data were analyzed using three methods: a visual reading of the raw ISI-CMAP curves and two computer-aided analyses of the regression curve fitting the ISI-CMAP plots. Pain induced by each technique was assessed on a 0-10 visual analogue scale. A test-retest study was performed with the PP techniques in 12 subjects. RESULTS: RP estimates varied with both the stimulation technique and the analysis method. The DC technique was more painful than the PP techniques, but provided shorter and more accurate ARP values, whereas the PP(sub) technique provided longer, but valid RRP values. Computer-aided methods of data analysis gave the lowest coefficients of test-retest variation. CONCLUSIONS: Compared to the PP techniques, the DC technique allowed the evaluation of the whole distribution of ARP estimates, not distorted by muscle fiber RPs. For RRP estimation, the PP(sub) technique can be preferred to the PP(supra) technique. Finally, computer-aided methods are preferable to analyze ISI-CMAP curves. SIGNIFICANCE: The distribution of RP estimates can be easily and reliably assessed in whole motor nerve trunks of humans, providing valuable information to assess peripheral nerve excitability.

Central and peripheral fatigue after electrostimulation-induced resistance exercise.

PURPOSE: To investigate central and peripheral fatigue induced by a typical session of electromyostimulation (EMS) of the triceps surae muscle. METHODS: A series of neuromuscular tests including voluntary and electrically evoked contractions were performed before and immediately after 13 min of EMS (75 Hz) in 10 healthy individuals. RESULTS: Maximal voluntary contraction torque of the plantar flexor muscles significantly decreased (-9.4%; P < 0.001) after EMS, and this was accompanied by an impairment of central activation, as attested by twitch interpolation results (P < 0.05), whereas soleus maximal Hoffmann reflex and tibialis anterior coactivation did not change significantly. Contractile properties associated with paired stimuli and maximal M-wave amplitude for both soleus and medial gastrocnemius muscles (-9.4 and -38.7%, respectively) were significantly affected by EMS (P < 0.05), whereas postactivation potentiation did not change. CONCLUSION: A single bout of EMS resulted in fatigue attributable to both central and peripheral factors. The most obvious alteration in the function of the central nervous system is a decrease in the quantity of the neural drive to muscle from the supraspinal centers. On the other hand, neuromuscular propagation failure was more evident for the muscle with the higher percentage of Type II fibers.

Potassium and the excitability properties of normal human motor axons in vivo.

Hyperkalemia is an important cause of membrane depolarization in renal failure. A recent theoretical model of axonal excitability explains the effects of potassium on threshold electrotonus, but predicts changes in superexcitability in the opposite direction to those observed. To resolve this contradiction we assessed the relationship between serum potassium and motor axon excitability properties in 38 volunteers with normal potassium levels. Most threshold electrotonus measures were strongly correlated with potassium, and superexcitability decreased at higher potassium levels (P = 0.016), contrary to the existing model. Improved modelling of potassium effects was achieved by making the potassium currents obey the constant-field theory, and by making the potassium permeabilities proportional to external potassium, as has been observed in vitro. This new model also accounted well for the changes in superexcitability and other excitability measures previously reported in renal failure. These results demonstrate the importance of taking potassium levels into account when assessing axonal membrane dysfunction by excitability testing, and provide evidence that potassium currents are activated by external potassium in vivo.

Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome.

Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency.

Validity of multi-fiber muscle velocity recovery cycles recorded at a single site using submaximal stimuli.

OBJECTIVE: To examine the validity of multi-fiber muscle velocity recovery cycles (VRCs) recorded by direct muscle stimulation with submaximal stimuli. METHODS: VRCs were recorded from tibialis anterior muscle in normal volunteers with 1, 2 and 5 conditioning stimuli. Recordings were made with 6 different amplitudes of conditioning stimuli. Recordings were also made with two recording electrodes, at least 15mm apart. RESULTS: Muscle VRCs in 6 subjects were not significantly different for conditioning stimuli between 80% and 150% of test stimulus amplitude. When recorded at two sites in 9 subjects, VRCs were similar when estimated over the shorter distance, the longer distance, and from the conduction time between the two electrodes. CONCLUSIONS: Multi-fiber muscle VRCs can be reliably recorded with a single recording electrode and with equal amplitude conditioning and test stimuli. SIGNIFICANCE: Clinical neurophysiologists can be assured that this new method of testing muscle membrane properties provides valid and robust measurements on normal muscles.

Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy.

Intravenous immunoglobulin (IVIg) infusions may provide clinical benefits in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). The short delay in the clinical response to IVIg therapy is not consistent with a process of remyelination or axonal regeneration. We assessed whether or not the efficacy of IVIg infusions in MMN and CIDP could reflect changes in axonal membrane properties and nerve excitability. Ulnar motor nerve excitability was studied before and after three to five consecutive days of IVIg infusions (0.4 g/kg/day) in 10 patients with MMN, 10 patients with CIDP, and 10 neurological controls (CTRLs). Excitability recovery cycle, stimulus-response and strength-duration properties were investigated. The recovery cycle parameters (absolute and relative refractory period durations, refractoriness and supernormality) were similar in all groups and did not change after IVIg infusions. At baseline, patients with CIDP, but not with MMN, showed a reduced strength-duration time constant (chronaxie) and increased rheobase when compared to CTRLs. After IVIg infusions, strength-duration time constant remained stable in CTRLs, but decreased in patients with MMN or CIDP. Rheobase increased in the three groups after treatment. The decreased strength-duration time constant after IVIg infusions in patients with MMN or CIDP could reflect a reduction of persistent Na(+) current, able to limit intraaxonal Na(+) accumulation and then to produce neuroprotective effects. However, this could also reflect compensatory mechanisms that did not directly underlie the therapeutic effect. Whatever the underlying process, this result revealed that IVIgs were able to produce early nerve excitability changes.

[Inflammatory demyelinating neuropathies: classification, evolution and prognosis]. / Neuropathies démyélinisantes inflammatoires. Classification, évolution et pronostic.

Inflammatory demyelinating neuropathies can be classified according to the topography of the nervous lesion. Acute and chronic polyradiculoneuritis are characterized by diffuse and multifocal, but predominantly proximal lesions, multifocal motor and sensory-motor neuropathies with persistent conduction blocks are restricted to some nerve trunks, while neuropathies due to monoclonal IgM with anti-MAG (Myelin Associated Glycoprotein) activity show distal and symmetric distribution. The clinical characteristics of inflammatory demyelinating neuropathies vary according to the type of neuropathy. Their course can be remittent or progressive but is especially marked by the risk of definitive axonal lesions, source of permanent neurological deficits. These neuropathies correspond to various mechanisms, which can be differentiated according to the antigenic target, the type of immunological disorder (with respect to cellular or humoral predominance), and the adapted therapeutic strategy. The inflammatory process is accompanied by energetic failure, leading to Na+/K+ pump impairment and intra-axonal Na+ accumulation. This failure results in Na+/Ca2+ exchanger activation, provoking neuronal Ca2+ influx, enzymatic proteolysis and axonal degeneration.