Na<Superscript>+</Superscript>,K<Superscript>+</Superscript>-ATPase activity in an animal model of mania

We evaluated Na⁺,K⁺-ATPase activity in hippocampus of rats submitted to an animal model of mania which included the use of lithium and valproate. In the acute treatment, amphetamine or saline was administered to rats for 14 days, between day 8 and 14, rats were treated with lithium, valproate or saline. In the maintenance treatment, rats were treated with lithium, valproate or saline, between day 8 and 14, amphetamine or saline were administered. Locomotor activity was assessed by open field test and Na⁺,K⁺-ATPase activity was measured. Our results showed that mood stabilizers reversed and prevented amphetamine-induced behavioral effects. Moreover, amphetamine (acute treatment) increased Na⁺,K⁺-ATPase activity, and administration of lithium or valproate reversed this effect. In the maintenance treatment, amphetamine increased Na⁺,K⁺-ATPase activity in saline-pretreated rats. Amphetamine administration in lithium- or valproate-pretreated animals did not alter Na⁺,K⁺-ATPase activity. The findings suggest that amphetamine-induced hyperactivity may be associated with an increase in Na⁺,K⁺-ATPase.     

Severe Hyperhomocysteinemia Decreases Respiratory Enzyme and Na<Superscript>+</Superscript>-K<Superscript>+</Superscript> ATPase Activities,and Leads to Mitochondrial Alterations in Rat Amygdala

Severe hyperhomocysteinemia is caused by increased plasma levels of homocysteine (Hcy), a methionine derivative, and is associated with cerebral disorders. Creatine supplementation has emerged as an adjuvant to protect against neurodegenerative diseases, due to its potential antioxidant role. Here, we examined the effects of severe hyperhomocysteinemia on brain metabolism, and evaluated a possible neuroprotective role of creatine in hyperhomocysteinemia, by concomitant treatment with Hcy and creatine (50 mg/Kg body weight). Hyperhomocysteinemia was induced in young rats (6-day-old) by treatment with homocysteine (0.3–0.6 µmol/g body weight) for 23 days, and then the following parameters of rat amygdala were evaluated: (1) the activity of the respiratory chain complexes succinate dehydrogenase, complex II and cytochrome c oxidase; (2) mitochondrial mass and membrane potential; (3) the levels of necrosis and apoptosis; and (4) the activity and immunocontent of Na⁺,K⁺-ATPase. Hcy treatment decreased the activities of succinate dehydrogenase and cytochrome c oxidase, but did not alter complex II activity. Hcy treatment also increased the number of cells with high mitochondrial mass, high mitochondrial membrane potential, and in late apoptosis. Importantly, creatine administration prevented some of the key effects of Hcy administration on the amygdala. We also observed a decrease in the activity and immunocontent of the α1 subunit of the Na⁺,K⁺-ATPase in amygdala after Hcy- treatment. Our findings support the notion that Hcy modulates mitochondrial function and bioenergetics in the brain, as well as Na⁺,K⁺-ATPase activity, and suggest that creatine might represent an effective adjuvant to protect against the effects of high Hcy plasma levels.     

Evaluation of brain creatine kinase activity in an animal model of mania induced by ouabain

Bipolar disorder (BD) is a common and severe mood disorder associated with higher rates of suicide and disability. The development of new animal models, and the investigation employing those available have extensively contributed to understand the pathophysiological mechanisms of BD. Intracerebroventricular (i.c.v.) administration of ouabain, a specific Na⁺,K⁺-ATPase inhibitor, has been used as an animal model for BD. It has been demonstrated that Na⁺,K⁺-ATPase is altered in psychiatric disorders, especially BD. Creatine kinase (CK) is important for brain energy homeostasis by exerting several integrated functions. In the present study, we evaluated CK activity in the striatum, prefrontal cortex and hippocampus of rats subjected to i.c.v. administration of ouabain. Adult male Wistar rats received a single i.c.v. administration of ouabain (10⁻² and 10⁻³ M) or vehicle (control group). Locomotor activity was measured using the open field test. CK activity was measured in the brain of rats immediately (1 h) and 7 days after ouabain administration. Our results showed that spontaneous locomotion was increased 1 h after ouabain administration and that hyperlocomotion was also observed 7 days after that. Moreover, CK activity was inhibited immediately after the administration of ouabain in the striatum, hippocampus and prefrontal cortex. Moreover, the enzyme was not affected in the striatum and hippocampus 7 days after ouabain administration. On the other hand, an inhibition in CK activity in the prefrontal cortex was observed. If inhibition of CK also occurs in BD patients, it will be tempting to speculate that the reduction of brain metabolism may be related probably to the pathophysiology of this disease.     

Endogenous modulators of brain Na, K-atpase at early postnatal stages of rat development

The presence of endogenous modulators (peaks I and II) of synaptosomal Na⁺, K⁺-ATPase activity from adult rat cerebral cortex was previously suggested. In this study, the presence of such modulators at different postnatal stages of rat development was examined and their effect was tested on Na⁺, K⁺-ATPase activity. Synaptosomal membrane Na⁺, K⁺-ATPase activity was enhanced 20–30% by peak I and inhibited 70–75% by peak II obtained from 4-, 10-, 20- and 35–40-day-old rats. A fraction purified from peak II by anionic exchange HPLC (termed II-E) highly inhibits enzyme activity and behaves as a ouabain-like factor. Inhibitory activity of a 4-day-old II-E fraction proved higher than the corresponding fraction obtained from adult rats. Since expression of cerebral Na⁺, K⁺-ATPase has been shown to increase 10-fold during development whereas peak II concentration was observed to remain constant, and given the higher potency of purified neonatal II-E fraction, the effect of the latter may be greater at early postnatal stages of development than during adult life. It is suggested that the II-E fraction, which contains an ouabain-like factor, may play a role in neuronal development.     

A G301R Na<Superscript>+</Superscript>/K<Superscript>+</Superscript>-ATPase mutation causes familial hemiplegic migraine type 2 with cerebellar signs

Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with hemiparesis during the aura. In over 50% of cases the causative gene is CACNA1A (FHM1), which in some cases produces a phenotype with cerebellar signs, including ataxia and nystagmus. Recently, mutations in ATP1A2 on chromosome 1q23 encoding a Na⁺/K⁺-ATPase subunit were identified in four families (FHM2). We now describe an FHM2 pedigree with a fifth ATP1A2 mutation coding for a G301R substitution. The phenotype was particularly severe and included hemiplegic migraine, seizure, prolonged coma, elevated temperature, sensory deficit, and transient or permanent cerebellar signs, such as ataxia, nystagmus, and dysarthria. A mild crossed cerebellar diaschisis during an attack further supported the clinical evidence of a cerebellar deficit. This is the first report suggesting cerebellar involvement in FHM2. A possible role for CACNA1A in producing the phenotype in this family was excluded by linkage studies to the FHM1 locus. The study of this family suggests that the absence of cerebellar signs may not be a reliable indicator to clinically differentiate FHM2 from FHM1.     

Effects of a chronic exposure to a highly palatable diet and its withdrawal,in adulthood,on cerebral Na,K-ATPase and plasma S100B in neonatally handled rats

We have previously demonstrated that early environment influences the metabolic response, affecting abdominal fat deposition in adult female rats exposed to a long-term highly caloric diet. In the present study, our goal was to verify the effects of the chronic exposure, in adulthood, to a highly palatable diet (chocolate) on cerebral Na⁺,K⁺-ATPase activity and S100B protein concentrations, and the response to its withdrawal in neonatally handled and non-handled rats. We measured the consumption of foods (standard lab chow and chocolate), body weight gain, S100B protein concentrations, as well as cerebral Na⁺,K⁺-ATPase activity during chronic exposure and after chocolate withdrawal in adult female rats that had been exposed or not to neonatal handling (10 min/day, 10 first days of life). Non-handled rats chronically exposed to chocolate exhibited increased plasma S100B levels, but there was no difference in abdominal fat S100B concentration between groups. Chronic chocolate consumption decreased Na⁺,K⁺-ATPase activity in both amygdala and hippocampus in non-handled, but not in handled rats, and this effect disappeared after chocolate withdrawal. Non-handled animals also demonstrated increased frequency of head shaking in the open field after 24 h of chocolate withdrawal in comparison to handled ones. These findings suggest that neonatal handling modifies the vulnerability to metabolic and brain alterations induced by chronic exposure to a highly palatable diet in adulthood.     

Brain Na, K-ATPase activity possibly regulated by a specific serotonin receptor

Na⁺, K⁺-ATPase activity in 6 regions of adult brain was measured after incubation with varying concentrations of serotonin. A concentration-dependent increase in enzyme activity was observed in 4 regions, with cerebral cortex and cerebellum showing the largest response. These results together with previous ones suggest that serotoninmmodulates brain Na⁺, K⁺-ATPase activity through a specific receptor located in target neurons or glial cells.     

Biogenesis of surface domains in fly photoreceptor cells: Fine-structural analysis of the plasma membrane and immunolocalization of Na+,K+ ATPase and α-spectrin during cell differentiation

Electron microscopic examination of pupal and adult blowfly (Calliphora erythrocephala) retina provides novel details on the biogenesis of the photoreceptor surface, particularly regarding the development of the microvillar rhabdomere and associated structures, such as the submicrovillar endoplasmic reticulum. Localization of the Na⁺,K⁺-ATPase on the surface of developing photoreceptors has also been examined by immunofluorescence confocal microscopy and immunogold electron microscopy. Na⁺,K⁺-ATPase has a nonpolarized distribution in midpupal photoreceptors that are determined by fate but that are not yet completely differentiated. Large amounts of Na⁺,K⁺-ATPase are synthesized and delivered to the cell surface throughout the second half of pupal life. At certain time points in late pupal development, specific membrane domains become cleared of Na⁺,K⁺-ATPase in the photoreceptors R1–R6. However, the distribution of Na⁺,K⁺-ATPase remains nonpolarized in R7/R8, even after eclosion. Because the membrane-associated cytoskeleton plays a direct role in the establishment and maintenance of membrane domains in a variety of systems, it is of interest to study the distribution of α-spectrin and its possible association with Na⁺,K⁺-ATPase. The localization of α-spectrin resembles the distribution pattern of Na⁺,K⁺-ATPase in midpupal and adult photoreceptors. However, changes in Na⁺,K⁺-ATPase localization in late pupal photoreceptors precede the redistribution of α-spectrin by several days. Biochemical studies of cellular membranes demonstrate further that Na⁺,K⁺-ATPase can be solubilized by Triton X-100, although α-spectrin remains in a macromolecular complex. These results indicate that the development and the maintenance of the polarized Na⁺,K⁺-ATPase distribution in blowfly photoreceptors are not tightly coupled to α-spectrin. © 1997 Wiley-Liss Inc.     

Effects of Dibutyryl Cyclic AMP on Na+, K+-ATPase Activity and Intracellular Na+ and K+ in Primary Cultures of Astrocytes from DBA and C57 Mice

Summary: Effects of chronic treatment of dibutyryl cyclic AMP (db-cyclic AMP) on Na⁺, K⁺-ATPase activity in cell homogenates and intracellular N a f and K+ contents [(Na⁺)_i and (K⁺)_i] were studied in primary cultures of astrocytes derived from cerebral cortex of neonatal audiogenic seizure-susceptible DBA and audiogenic seizure-resistant C57 mice. Na⁺, K⁺-ATPase activity in cell homogenates was greater and (Na⁺)_i was less in DBA astrocytes than in C57 astrocytes. There was no difference in (K⁺)_i between astrocytes from DBA and C57 mice. Addition of db-cyclic AMP to the medium from day 14 to day 21 in culture (final concentration 0.25 mM) increased Na⁺, K⁺-ATPase activity in cell homogenates and decreased (Na⁺)_i, but had no significant effect on (K⁺)_i in astrocytes from either DBA or C57 mice. Chronic treatment with db-cyclic AMP altered cell growth. Protein and DNA content of cultured astrocytes from both DBA and C57 mice was decreased. DNA was more affected than protein. Modifying K⁺ and Na⁺ concentration in medium altered Na⁺, K⁺-ATPase activity in cell homogenates as well as (Na⁺)_i and (K⁺)_i in cultured astrocytes of both DBA and C57 mice. Changes in (Na⁺)_i and (K⁺)_i at different K⁺ concentrations in medium paralleled those in Na⁺, K⁺-ATPase activity in cell homogenates. Results indicate that the ability to transport Na⁺ across the cell membrane and the response of Na⁺, K⁺-ATPase to db-cyclic AMP and to the changes in K + in medium of cultured astrocytes from audiogenic seizure-susceptible DBA mice are sufficient.     

Alterations of cerebromicrovascular Na, K-ATPase activity due to fatty acids and acute hypertension

Acute hypertension, induced in rats by intravenous injection of angiotensin II, previously has been shown to increase cerebrovascular permeability to macromolecules. The purpose of this study was to examine the effect of acute hypertension on Na⁺, K⁺-ATPase, the enzyme responsible for controlling ionic permeability of the cerebromicrovascular endothelium. The K⁺-dependent p-nitrophenylphosphatase activity of the cerebromicrovascular Na⁺, K⁺-ATPase was determined using microvessels prepared from hypertensive and normotensive rats. When compared to controls, a 70% decrease (P < 0.02) in the maximum rate (V_max) of the Na⁺, K⁺-ATPase from hypertensive rats was evident with no change in the Michaelis constant (K_M). In contrast, γ-glutamyltranspeptidase, a marker enzyme for cerebral endothelic cells, was not significantly affected. Sodium arachidonate (1–100 μM) inhibited the phosphatase activity of the Na⁺, K⁺-ATPase in microvessels isolated from both normotensive and hypertensive rats in a dose-dependent manner. Furthermore, poly-unsaturated fatty acids (sodium linoleate and arachidonate) evoked the greatest inhibition of the enzyme, while sodium oleate and sodium palmitate inhibited the Na⁺, K⁺-ATPase to lesser extents. This regulation of enzyme activity by fatty acids was comparable in control and hypertensive groups. In summary, the data indicate that the cerebromicrovascular Na⁺, K⁺-ATPase was altered as a consequence of acute hypertension and that poly-unsaturated fatty acids can modulate this enzyme in microvessels derived from hypertensive or control rats     

Erythrocyte membrane sodium — potassium adenosine triphosphatase activity in affective disorders

Summary Erythrocyte membrane Na⁺,K⁺-ATPase activity was studied in drug naive patients with bipolar (BP) mania (n=62) and unipolar (UP) depression (n=60) and normal controls (n=66). Compared to controls there was a significantly decreased Na⁺,K⁺-ATPase activity in UP depressives but no change in BP manics. However, lithium treatment caused a significant increase in Na⁺,K⁺-ATPase activity although there was no correlation between plasma lithium levels and enzyme activity. Plasma cortisol correlated inversely with Na⁺,K⁺-ATPase in UP depressives. Interestingly, the lithium responders [<50% Beck Rafaelson's Mania Rating Scale (BRMS) score] showed a significant increase in Na⁺,K⁺-ATPase activity compared to lithium nonresponders (>50% BRMS score). These observations indicate that monitoring of Na⁺,K⁺-ATPase activity during lithium therapy is useful to predict a therapeutic response.     

Long-term decrease in Na,K-ATPase activity after pilocarpine-induced status epilepticus is associated with nitration of its alpha subunit

Temporal lobe epilepsy (TLE) is the most common type of epilepsy with about one third of TLE patients being refractory to antiepileptic drugs. Knowledge about the mechanisms underlying seizure activity is fundamental to the discovery of new drug targets. Brain Na⁺,K⁺-ATPase activity contributes to the maintenance of the electrochemical gradients underlying neuronal resting and action potentials as well as the uptake and release of neurotransmitters. In the present study we tested the hypothesis that decreased Na⁺,K⁺-ATPase activity is associated with changes in the alpha subunit phosphorylation and/or redox state. Activity of Na⁺,K⁺-ATPase decreased in the hippocampus of C57BL/6 mice 60 days after pilocarpine-induced status epilepticus (SE). In addition, the Michaelis–Menten constant for ATP of α2/3 isoforms increased at the same time point. Nitration of the α subunit may underlie decreased Na⁺,K⁺-ATPase activity, however no changes in expression or phosphorylation state at Ser⁹⁴³ were found. Further studies are necessary define the potential of nitrated Na⁺,K⁺-ATPase as a new therapeutic target for seizure disorders.     

Peripheral Administration of Tetanus Toxin Hc Fragment Prevents MPP<Superscript>+</Superscript> Toxicity In Vivo

Several studies have shown that intrastriatal application of 1-methyl-4-phenylpyridinium (MPP⁺) produces similar biochemical changes in rat to those seen in Parkinson’s disease (PD), such as dopaminergic terminal degeneration and consequent appearance of motor deficits, making the MPP⁺ lesion a widely used model of parkinsonism in rodents. Previous results from our group have shown a neuroprotective effect of the carboxyl-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) under different types of stress. In the present study, pretreatment with the intraperitoneal injection of Hc-TeTx in rats prevents the decrease of tyrosine hydroxylase immunoreactivity in the striatum due to injury with MPP⁺, when applied stereotaxically in the striatum. Similarly, striatal catecholamine contents are restored, as well as the levels of two other dopaminergic markers, the dopamine transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2). Additionally, uptake studies of [³H]-dopamine and [³H]-MPP⁺ reveal that DAT action is not affected by Hc-TeTx, discarding a protective effect due to a reduced entry of MPP⁺ into nerve terminals. Behavioral assessments show that Hc-TeTx pretreatment improves the motor skills (amphetamine-induced rotation, forelimb use, and adjusting steps) of MPP⁺-treated rats. Our results lead us to consider Hc-TeTx as a potential therapeutic tool in pathologies caused by impairment of dopaminergic innervation in the striatum, as is the case of PD.     

Membrane desmosterol and the kinetics of the sarcolemmal Na,K-ATPase in myotonia induced by 20,25-diazacholesterol

The kinetics of the sarcolemmal Na⁺,K⁺-ATPase were studied in rats made myotonic by treatment with 20,25-diazacholesterol (20,25-D; 200 mg/kg every 14 days). Overall Na⁺,K⁺-ATPase activity in purified sarcolemma increased from 44.6 ± 8.7 nmol P_i/mg protein⁻¹ min⁻¹ in controls to 77.7 ± 7.9 nmol mg⁻¹ min⁻¹ in treated animals whose membrane desmosterol concentrations exceeded 70% of total membrane sterol. In general the activity of this enzyme paralleled the desmosterol content of the sarcolemma. The total number of enzyme units, however, was not changed as evidenced by [³H]ouabain binding and by measurements of steady-state phosphorylated intermediate in the absence of K⁺. Independent measurements of the Na⁺,K⁺-ATPase dephosphorylation partial reaction in 20,25-D sarcolemma revealed no change from control rats at any temperature between 5 and 40°C; the K⁺ dependence of this reaction was also unchanged. Rates of phosphoprotein formation inferred from measurements of steady-state phosphorylated intermediate under various ionic conditions were also not altered by increasing desmosterol. Kinetic analysis suggests that the increase in overall Na⁺,K⁺-ATPase activity in membranes with high concentrations of desmosterol may reflect an increase in the rate of conformational interchange between two states of the enzyme during its activity cycle.     

Intracerebroventricular ouabain administration induces oxidative stress in the rat brain

Intracerebroventricular (ICV) injection of ouabain (a potent Na⁺/K⁺-ATPase inhibitor) in rats resulted in manic-like effects. There is an emerging body of data indicating that major neuropsychiatric disorders, such as bipolar disorder and schizophrenia, are associated with increased oxidative stress. In this study, we investigated the effects of ICV ouabain injection on oxidative stress parameters in total tissue of rat brain. Our findings demonstrated that ICV injection increased thiobarbituric acid reactive species levels and protein carbonyl generation in the prefrontal cortex and hippocampus of rats. Moreover, the activity of the antioxidants enzymes catalase and superoxide dismutase was altered in several areas of the rat brain and cerebrospinal fluid of ICV ouabain-subjected rats. These results showed that Na⁺/K⁺-ATPase inhibition can lead to oxidative stress in the brain of rats.     

Control of the Na+, K+-ATPase under normal and pathological conditions

The Na⁺, K⁺-ATPase is an important enzyme in determining the ionic milieu of the cerebromicrovasculature and neurons. The effect of hypertension or aging on this enzyme, as well as its susceptibility to regulation by fatty acids or aluminum, is the focus of this study. A significant increase (34%) in the apparent affinity constant (K _D) but no change in the maximum binding capacity (B _max) for [³H]ouabain binding to the cerebromicrovascular Na⁺, K⁺-ATPase occurs after induction of acute hypertension. In addition, long chain unsaturated fatty acids stimulate the binding of [³H]ouabain to the enzyme in microvessels from normotensive and hypertensive rats. The synaptosomal Na⁺, K⁺-ATPase is sensitive to aluminum. AlCl₃ (1–100 μM) inhibits the K⁺-dependent-p-nitrophenylphosphatase (K⁺-NPPase) activity of the Na⁺, K⁺-ATPase in a dose-dependent manner. AlCl₃ (100 μM) decreases theV _max by 14% but does not alter theK _M, suggestive of noncompetitive inhibition. The enzyme from aged brain displays a greaterV _max, but shows the same susceptibility to AlCl₃ as the enzyme from younger brain. In summary, disruption of the Na⁺, K⁺-ATPase may underlie, at least in part, abnormalities of nerve and vascular cell function in disorders where elevated concentrations of fatty acids or metal ions are involved.     

Glial contribution to seizure: K activation of (Na, K)-ATPase in bulk isolated glial cells and synaptosomes of epileptogenic cortex

Glial and neuronal (Na⁺, K⁺)-ATPase have dissimilar apparent affinities for K⁺ ions. Glial (Na⁺, K⁺)-ATPase is maximally activated by 20 mM K⁺ while neuronal (Na⁺, K⁺)-ATPase is maximally stimulated by 3–5 mM K⁺. Because this glial property may play an important role in the clearance of [K⁺]₀ during seizures, we investigated the K⁺ activation of (Na⁺, K⁺)-ATPase within bulk isolated glial cells and synaptosomes isolated from epileptogenic brains. The primary focus (F), the homolateral brain area around the focus (PF) and the mirror (M) or secondary focus induced by freezing lesions were studied.Results show that both glial and synaptosomal enzyme activities in the epileptogenic state change in comparison with controls, i.e. sham-operated cats. In F and M., glial enzyme decreased reaction velocities between 3 and 18 mM K⁺. In PF, maximum velocities increased in glial (Na⁺, K⁺)-ATPase. These results indicate that in actively firing epileptogenic tissue (F, M), glial (Na⁺, K⁺)-ATPase decreased rate reactions while the catalytic activity was increased in cortical tissues surrounding the focus. These phenomena appeared early, i.e. 1–3 days after production of the freezing lesion, and was associated with a sharp decrease in absolute levels of enzyme activity.Synaptosomal (Na⁺, K⁺)-ATPase from controls always exhibited a saturation curve at 3–6 mM K⁺. Synaptosomal enzyme activities in the primary (F) lesion increased slightly 24 h after lesion production, then progressively decreased 3 days after lesion production. No significant changes were seen in M and PF.     

Dexamethasone suppresses infiltration of RhoA<Superscript>+</Superscript> cells into early lesions of rat traumatic brain injury

Inflammatory cell infiltration is a major part of secondary tissue damage in traumatic brain injury (TBI). RhoA is an important member of Rho GTPases and is involved in leukocyte migration. Inhibition of RhoA and its downstream target, Rho-associated coiled kinase (ROCK), has been proven to promote axon regeneration and function recovery following injury in the central nervous system (CNS). Previously, we showed that dexamethasone, an immunosuppressive corticosteroid, attenuated early expression of three molecules associated with microglia/macrophages activation following TBI in rats. Here, the effects of dexamethasone on the early expression of RhoA have been investigated in brains of TBI rats by immunohistochemistry. In brains of rats treated with TBI alone, significant RhoA⁺ cell accumulation was observed at 18 h post-injury and continuously increased during our observed time period. The accumulated RhoA⁺ cells were distributed to the areas of pannecrosis and selective neuronal loss. Most accumulated RhoA⁺ cells were identified as active microglia/macrophages by double-labelling. Dexamethasone (1 mg/kg body weight) was intraperitoneally injected on day 0 and 2 immediately following brain injury. Numbers of RhoA⁺ cells were significantly reduced on day 1 and 2 following administration of dexamethasone but returned to vehicle control level on day 4. However, dexamethasone treatment did not change the proportion of RhoA⁺ cells. These observations suggest that dexamethasone has only a transient effect on early leukocyte recruitment.     

Endoneurial ATPase activity in tangier disease and other peripheral neuropathies

Endoneurial sodium, potassium adenosine triphosphatase (Na⁺, K⁺-ATPase) and Mg²⁺-ATPase activities were determined in routine sural nerve biopsies from patients being evaluated for peripheral neuropathy. A significant reduction of endoneurial Na⁺, K⁺-ATPase and Mg²⁺-ATPase activities was shown in six sural nerve biopsies from patients with Tangier disease complicated by mononeuopathy multiplex or progressive axonal neuropathy. Peripheral nerve ATPase activities did not correlate with myelinated or unmyelinated nerve fiber densities in these biopsies. Other peripheral neuronal disorders with reduced endoneurial Na⁺, K⁺-ATPase and Mg²⁺-ATPase activities included severe vasculitic neuropathy, diabetic neuropathy, tomaculous neuropathy, and motoneuron disease. Such reduced levels of ATPase activity in peripheral nerve may relate to altered endoneurial lipid metabolism and impaired axoplasmic flow.