[Persistent abdominal pain caused by superior mesenteric artery and celiac trunk dissection that does not respond to conservative treatment]. / Dolor abdominal persistente por disección de arteria mesentérica superior y tronco celiaco, que no responde a tratamiento conservador.

We report the case of a 32 year old male with recurrent colic abdominal pain due to superior mesenteric artery (SMA) and celiac trunk dissection, which resolved after placing 3 stents in SMA. The patient presented atypical clinical signs and symptoms, which made the diagnosis difficult. Clinical presentation, diagnostic methods and treatment options are discussed. We started with conservative management with pain medication, anticoagulation, antihypertensive drugs and image control, but on the seventh day, after restarting oral ingestion, he presented with abdominal angina, after which we proceeded to endovascular treatment with successful results and with an uneventfully 2 year follow up.

Dolor abdominal persistente por disección de arteria mesentérica superior y tronco celiaco, que no responde a tratamiento conservador / Persistent abdominal pain caused by superior mesenteric artery and celiac trunk dissection that does not respond to conservative treatment

Reportamos el caso de un paciente varón de 32 años con dolor abdominal recurrente tipo cólico a causa de disección de arteria mesentérica superior (AMS) y tronco celíaco, el cual se resolvió luego de la colocación de 3 stents en AMS. El paciente presentó una clínica atípica lo cual dificultó el diagnóstico. Discutimos la clínica, métodos diagnósticos y alternativas de tratamiento. Iniciamos con un manejo conservador con analgesia, anticoagulación plena, antihipertensivo y control de imágenes, pero al séptimo día luego de reiniciar la vía oral, presenta angina abdominal, por lo cual procedimos a tratamiento endovascular con resultado exitoso y buena evolución, sin eventos, a un seguimiento de 2 años

We report the case of a 32 year old male with recurrent colic abdominal pain due to superior mesenteric artery (SMA) and celiac trunk dissection, which resolved after placing 3 stents in SMA. The patient presented atypical clinical signs and symptoms, which made the diagnosis difficult. Clinical presentation, diagnostic methods and treatment options are discussed. We started with conservative management with pain medication, anticoagulation, antihypertensive drugs and image control, but on the seventh day, after restarting oral ingestion, he presented with abdominal angina, after which we proceeded to endovascular treatment with successful results and with an uneventfully 2 year follow up

Drug-induced parkinsonism.

INTRODUCTION: Drug-induced parkinsonism (DIP) is the second most common cause of parkinsonism after idiopathic Parkinson's disease (iPD). Initially reported as a complication of antipsychotics, it was later recognized as a common complication of antidepressants, calcium channel antagonists, gastrointestinal prokinetics, antiepileptic drugs and many other compounds. Despite being a major health problem in certain populations, it seems to be frequently overlooked by the medical community. AREAS COVERED: This paper approaches the concept of DIP, reviews its epidemiology, clinical features and ancillary tests recommended for a correct diagnosis. The authors discuss the different drugs and its pathogenic mechanisms. The relevance of an early recognition and recommendations for a correct management are commented. EXPERT OPINION: Prescribers need to remain vigilant for DIP, particularly in the elderly, patients taking multiple drugs and those with genetic risk factors involved in iPD. Cessation of the causing agent is the main treatment and there is no evidence of benefit for the use of anticholinergics or levodopa. If the medication cannot be withdrawn, it should be switched to agents with a lower risk of DIP.

Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy.

Cannabinoids are neuroprotective in models of neurodegenerative dementias. Their effects are mostly mediated through CB1 and CB2 receptor-dependent modulation of excitotoxicity, inflammation, oxidative stress, and other processes. We tested the effects of Sativex®, a mixture of Δ9-tetrahydrocannabinol and cannabidiol, acting on both CB1 and CB2 receptors, in parkin-null, human tau overexpressing (PK-/-/TauVLW) mice, a model of complex frontotemporal dementia, parkinsonism, and lower motor neuron disease. The animals received Sativex®, 4.63 mg/kg, ip, daily, for one month, at six months of age, at the onset of the clinical symptoms. We evaluated the effects of Sativex® on behavior, dopamine neurotransmission, glial activation, redox state, mitochondrial activity, and deposition of abnormal proteins. PK-/-/TauVLW mice developed the neurological deficits, but those treated with Sativex® showed less abnormal behaviors related to stress, less auto and hetero-aggression, and less stereotypy. Sativex® significantly reduced the intraneuronal, MAO-related free radicals produced during dopamine metabolism in the limbic system. Sativex® also decreased gliosis in cortex and hippocampus, increased the ratio reduced/oxidized glutathione in the limbic system, reduced the levels of iNOS, and increased those of complex IV in the cerebral cortex. With regard to tau and amyloid pathology, Sativex® reduced the deposition of both in the hippocampus and cerebral cortex of PK-/-/TauVLW mice and increased autophagy. Sativex®, even after a short administration in animals with present behavioral and pathological abnormalities, improves the phenotype, the oxidative stress, and the deposition of proteins in PK-/-/TauVLW mice, a model of complex neurodegenerative disorders.

Parkin null cortical neuronal/glial cultures are resistant to amyloid-ß1-42 toxicity: a role for autophagy?

Dementia occurs often in late stages of Parkinson's disease (PD) but its cause is unknown. Likewise there is little information about the interaction between proteins that produce PD and those implicated in Alzheimer's disease (AD). Here we have investigated the interactions between parkin protein and the amyloid-ß (Aß)1-42 peptide. We examined the effects of oligomeric Aß1-42 peptide on the survival, differentiation, and signaling pathways in cortical cultures from wild type (WT) and parkin null (PK-KO) mice. We discovered that PK-KO cells were more resistant than WT to Aß1-42. This peptide induced neuronal cell death, astrogliosis, microglial proliferation, and increased total and hyperphosphorylated tau and levels of chaperones HSP-70 and CHIP in WT, but not in Aß-treated PK-KO cultures. Aß1-42 decreased proteasome activities in WT and PK-KO cultures, but the ubiquitination of proteins only increased in WT cultures. Aß1-42 induced a short activation of ERK1/2 and AKT signaling pathways, implicated in cell survival, in PK-KO-treated cells, and a shift in the autophagy marker LC3-II/LC3-I ratio. In addition, the percentage of cells immunoreactive to both HSC70 and LAMP-2A increased in PK-KO cultures versus WT and furthermore in PK-KO cultures treated with Aß1-42. Pre-treatment with inhibitors of glutathione synthesis or autophagy reverted the resistance to Aß1-42 of the PK-KO cultures. In conclusion, the loss of parkin protein triggers the compensatory mechanisms of cell protection against Aß1-42. Parkin suppression, therefore, is not a risk factor for dementia of AD type.

Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP(swe) mutant mice.

There is an open controversy about the role of surgery and anesthesia in the pathogenesis of Alzheimer's disease (AD). Clinical studies have shown a high prevalence of these procedures in subjects with AD but the interpretation of these studies is difficult because of the co-existence of multiple variables. Experimental studies in vitro and in vivo have shown that small molecular weight volatile anesthetics enhance amyloidogenesis in vitro and produce behavioral deficits and brain lesions similar to those found in patients with AD. We examined the effect of co-treatment with trehalose on isoflurane-induced amyloidogenesis in mice. WT and APP(swe) mice, of 11 months of age, were exposed to 1% isoflurane, 3 times, for 1.5 hours each time and sacrificed 24 hours after their last exposure to isoflurane. The right hemi-brain was used for histological analysis and the contra-lateral hemi-brain used for biochemical studies. In this study, we have shown that repetitive exposure to isoflurane in pre-symptomatic mature APP(swe) mice increases apoptosis in hippocampus and cerebral cortex, enhances astrogliosis and the expression of GFAP and that these effects are prevented by co-treatment with trehalose, a disaccharide with known effects as enhancer of autophagy. We have also confirmed that in our model the co-treatment with trehalose increases the expression of autophagic markers as well as the expression of chaperones. Cotreatment with trehalose reduces the levels of ß amyloid peptide aggregates, tau plaques and levels of phospho-tau. Our study, therefore, provides new therapeutic avenues that could help to prevent the putative pro-amyloidogenic properties of small volatile anesthetics.

Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation.

Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms. We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK(-/-)/Tau(VLW)). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine beta-amyloid in the hippocampus. Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK(-/-)/Tau(VLW) phenotype. The treatment with trehalose of 3-month-old PK(-/-)/Tau(VLW) mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK(-/-)/Tau(VLW) and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK(-/-)/Tau(VLW) mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK(-/-)/Tau(VLW) mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine beta-amyloid plaques. Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.

Anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer's disease.

There is a great interest in the environmental and genetic factors which modify the risk of Alzheimer's disease since the manipulation of these factors could help to change the prevalence and natural course of this disease. Among the first group, anesthesia and surgery have been considered as risk enhancers, based mostly on "in vitro" experiments and epidemiological studies. We have investigated the effects of repetitive anesthesia, twice a week, for 3 months, from 7 to 10 months of age, with isoflurane on survival, behavior, apoptosis in hippocampal cells, amyloid-beta (Abeta) peptide and tau patterns, chaperones and autophagy in WT and AbetaPP{swe} mice. We have found that AbetaPP{swe} mice treated with isoflurane have increased mortality, less responsiveness after anesthesia, long lasting reduced exploratory behavior, increased number of TUNEL{+} apoptotic cells, and increased ratio of pro-apoptotic proteins in hippocampus, reduced astroglial and increased microglial responses, increased Abeta aggregates and high molecular weight peptides, abnormal chaperone responses and reduced autophagy. These effects were not present in WT mice, suggesting that the deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with increased susceptibility but does not affect normal subjects.

The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice.

Parkin suppression induces accumulation of beta-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP(swe) mutant mice. We produced double mutant mice with human mutated APP(swe)+partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP(swe) overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK(+/-) and PK(-/-), respectively), and double mutants (APP/PK(+/-) and APP/PK(-/-)). APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK(+/-) and APP/PK(-/-) mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK(+/-) and APP/PK(-/-) mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK(+/-) and APP/PK(-/-) mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK(+/-) heterozygotic and homozygotic APP/PK(-/-) mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK(+/-) and APP/PK(-/-). Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK(-/-) mice. We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP(swe) mice.

Parkin deficiency increases the resistance of midbrain neurons and glia to mild proteasome inhibition: the role of autophagy and glutathione homeostasis.

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals and abnormal neurotransmitter release. In this study, we have investigated whether partial proteasomal inhibition by epoxomicin, an ubiquitin proteasomal system (UPS) irreversible inhibitor, further aggravates the cellular effects of parkin suppression in midbrain neurons and glia. We observed that parkin null (PK-KO) midbrain neuronal cultures are resistant to epoxomicin-induced cell death. This resistance is due to increased GSH and DJ-1 protein levels in PK-KO mice. The treatment with epoxomicin increases, in wild type (WT) cultures, the pro-apoptotic Bax/Bcl-2 ratio, the phosphorylation of tau, and the levels of chaperones heat-shock protein 70 and C-terminal Hsc-interacting protein, but none of these effects took place in epoxomicin-treated PK-KO cultures. Poly-ubiquitinated proteins increased more in WT than in PK-KO-treated neuronal cultures. Parkin accumulated in WT neuronal cultures treated with epoxomicin. Markers of autophagy, such as LC3II/I, were increased in naïve PK-KO cultures, and further increased after treatment with epoxomicin, implying that the blockade of the proteasome in PK-KO neurons triggers the enhancement of autophagy. The treatment with l-buthionine-S,R-sulfoximine and the inhibition of autophagy, however, reverted the increase resistance to epoxomicin of the PK-KO cultures. We also found that PK-KO glial cells, stressed by growth in defined medium and depleted of GSH, were more susceptible to epoxomicin induced cell death than WT glia treated similarly. This susceptibility was linked to reduced GSH levels and less heat-shock protein 70 response, and to activation of p-serine/threonine kinase protein signaling pathway as well as to increased poly-ubiquitinated proteins. These data suggest that mild UPS inhibition is compensated by other mechanisms in PK-KO midbrain neurons. However the depletion of GSH, as happens in stressed glia, suppresses the protection against UPS inhibition-induced cell death. Furthermore, GSH inhibition regulated differentially UPS activity and in old PK-KO mice, which have depletion of GSH, UPS activity is decreased in comparison with that of old-WT.

The multiple mechanisms of amyloid deposition: the role of parkin.

Amyloid deposition is one of the central neuropathological abnormalities in Alzheimer's disease (AD) but it also takes places in many neurodegenerative diseases such as prionic disorders, Huntington's disease (HD) and others. Up to very recently amyloid formation was considered a very slow process of deposition of an abnormal protein due to genetic abnormalities or post-translational modification of the deposited protein. Recent data suggest that the process of amyloidogenesis may be much more rapid in many cases and due to multiple mechanisms. We have found a mouse model of progressive neurodegeneration that resemble motor, behavioral and pathological hallmarks of parkinsonism and tauopathies, but surprisingly, also present amyloid deposits in brain and peripheral organs. Here we review some of these recent works which may provide new insight into the process of formation of amyloid and, perhaps, new ideas for its treatment.

Cannabinoid CB1 receptors are early downregulated followed by a further upregulation in the basal ganglia of mice with deletion of specific park genes.

This study was designed to examine the type of changes experienced by the CB1 receptor, a key element of the cannabinoid signaling system, in the basal ganglia of different mouse mutants generated by deletion of specific genes associated with the development of Parkinson's disease in humans [PARK1 (alpha-synuclein), PARK2 (parkin) or PARK6 (PINK1)]. We observed that CB1 receptor-mRNA levels were significantly reduced in the caudate-putamen in the three models under examination when animals were analyzed at early phases (< or = 12 months of age). This decrease was, in general, associated with a reduction in CB1 receptor binding in the substantia nigra and the globus pallidus, particularly in the case of alpha-synuclein-deficient mice. By contrast, both parameters, mRNA levels and binding for the CB1 receptor, showed an elevation in the same areas when animals were analyzed at older ages, mainly in the case of the CB1 receptor binding in the substantia nigra. In summary, our data revealed the existence of a biphasic response for CB1 receptors, with losses at early phases, when dopaminergic dysfunction is possibly the major event that takes place, followed by upregulatory responses at advanced phases characterized by the occurrence of evident nigrostriatal pathology including neuronal death in some cases.

Glial cells as players in parkinsonism: the "good," the "bad," and the "mysterious" glia.

The role of glia in Parkinson's disease (PD) is very interesting because it may open new therapeutic strategies in this disease. Traditionally it has been considered that astrocytes and microglia play different roles in PD: Astroglia are considered the "good" glia and have traditionally been supposed to be neuroprotective due to their capacity to quench free radicals and secrete neurotrophic factors, whereas microglia, considered the "bad" glia, are thought to play a critical role in neuroinflammation. The proportion of astrocytes surrounding dopamine (DA) neurons in the substantia nigra, the target nucleus for neurodegeneration in PD, is the lowest for any brain area, suggesting that DA neurons are more vulnerable in terms of glial support than any neuron in other brain areas. Astrocytes are critical in the modulation of the neurotoxic effects of many toxins that induce experimental parkinsonism and they produce substances in vitro that could modify the effects of L-DOPA from neurotoxic to neurotrophic. There is a great interest in the role of inflammation in PD, and in the brains of these patients there is evidence for microglial production of cytokines and other substances that could be harmful to neurons, suggesting that microglia of the substantia nigra could be actively involved, primarily or secondarily, in the neurodegeneration process. There is, however, evidence in favor of the role of neurotoxic diffusible signals from microglia to DA neurons. More recently a third glial player, oligodendroglia, has been implicated in the pathogenesis of PD. Oligodendroglia play a key role in myelination of the nervous system. Recent neuropathological studies suggested that the nigrostriatal dopamine neurons, which were considered classically as the primary target for neurodegeneration in PD, degenerate at later stages than other neurons with poor myelination. Therefore, the role of oligodendroglia, which also secrete neurotrophic factors, has entered the center of interest of neuroscientists.

Metabolic challenge to glia activates an adenosine-mediated safety mechanism that promotes neuronal survival by delaying the onset of spreading depression waves.

In a model of glial-specific chemical anoxia, we have examined how astrocytes influence both synaptic transmission and the viability of hippocampal pyramidal neurons. This relationship was assessed using electrophysiological, pharmacological, and biochemical techniques in rat slices and cell cultures, and oxidative metabolism was selectively impaired in glial cells by exposure to the mitochondrial gliotoxin, fluoroacetate. We found that synaptic transmission was blocked shortly after inducing glial metabolic stress and peri-infarct-like spreading depression (SD) waves developed within 1 to 2 h of treatment. Neuronal electrogenesis was not affected until SD waves developed, thereafter decaying irreversibly. The blockage of synaptic transmission was totally reversed by A(1) adenosine receptor antagonists, unlike the development of SD waves, which appeared earlier under these conditions. Such blockage led to a marked reduction in the electrical viability of pyramidal neurons 1 h after gliotoxin treatment. Cell culture experiments confirmed that astrocytes indeed release adenosine. We interpret this early glial response as a novel safety mechanism that allocates metabolic resources to vital processes when the glia itself sense an energy shortage, thereby delaying or preventing entry into massive lethal ischemic-like depolarization. The implication of these results on the functional recovery of the penumbra regions after ischemic insults is discussed.

Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice.

Deposition of proteins leading to amyloid takes place in some neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. Mutations of tau and parkin proteins produce neurofibrillary abnormalities without deposition of amyloid. Here we report that mature, parkin null, over-expressing human mutated tau (PK(-/-)/Tau(VLW)) mice have altered behaviour and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs. PK(-/-)/Tau(VLW) mice have abnormal behaviour and severe drop out of dopamine neurons in the ventral midbrain, up to 70%, at 12 months and abundant phosphorylated tau positive neuritic plaques, neuro-fibrillary tangles, astrogliosis, microgliosis and plaques of murine beta-amyloid in the hippocampus. PK(-/-)/Tau(VLW) mice have organomegaly of the liver, spleen and kidneys. The electron microscopy of the liver confirmed the presence of a fibrillary protein deposits with amyloid characteristics. There is also accumulation of mouse tau in hepatocytes. These mice have lower levels of CHIP-HSP70, involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis. This model is the first that demonstrates beta-amyloid deposits caused by over-expression of tau and without modification of the amyloid precursor protein, presenilins or secretases. PK(-/-)/Tau(VLW) mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease.

Gender differences and estrogen effects in parkin null mice.

Estrogens are considered neurotrophic for dopamine neurons. Parkinson's disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild-type (WT) and parkin null mice (PK-/-). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl-2/Bax, chaperones, and GSH), but some of these inter-sex differences disappear in PK-/-. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK-/- mice. Neuronal cultures from midbrain of WT and PK-/- mice were treated with estradiol from 10 min to 48 h. Short-term treatments activated the mitogen-activated protein kinase pathway of WT and PK-/- neurons and the phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase-3 pathway of WT but not of PK-/- cultures. Long-term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK-/- cultures. The levels of estrogen receptor-alpha were elevated in midbrain cultures and in the striatum of adult PK-/- male mice, suggesting that suppression of parkin changes the estrogen receptor-alpha turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin-related Parkinson's disease patients.

Glial dysfunction in parkin null mice: effects of aging.

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18-20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression. PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme gamma-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe2+ plus H2O2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

Mortality, oxidative stress and tau accumulation during ageing in parkin null mice.

Young parkin null (pk-/-) mice have subtle abnormalities of behaviour, dopamine (DA) neurotransmission and free radical production, but no massive loss of DA neurons. We investigated whether these findings are maintained while ageing. Pk-/- mice have reduced life span and age-related reduced exploratory behaviour, abnormal walking and posture, and behaviours similar to those of early Parkinson's disease (PD), reduced number of nigrostriatal DA neurons and proapoptotic shifts in the survival/death proteins in midbrain and striatum. Contrary to young pk-/- animals 24-month-old pk-/- mice do not have compensatory elevation of GSH in striatum, glutathione reductase (GR) and glutathione peroxidase (GPx) activities are increased and catalase unchanged. Aged pk-/- mice accumulate high levels of tau and fail to up-regulate CHIP and HSP70. Our results suggest that aged pk-/- mice lack of the compensatory mechanisms that maintain a relatively normal DA function in early adulthood. This study could help to explain the effects of ageing in patients with genetic risks for Parkinson's disease.

Drug-induced parkinsonism.

Drug-induced parkinsonism (DIP) is the second cause of akinetic rigid syndrome in the Western world and its prevalence is increasing and approaching that of idiopathic Parkinson's disease due to the ageing of the population and to the rising of polypharmacotherapy. DIP was initially reported as a complication of neuroleptics in psychiatric patients, but it has also been described with a great diversity of compounds such as antiemetics, drugs used for the treatment of vertigo, antidepressants, calcium channel antagonists, antiarrythmics, antiepileptics, cholinomimetics and other drugs. Although traditionally considered reversible, DIP may persist after drug withdrawal. At least 10% of patients with DIP develop persistent and progressive parkinsonism in spite of the discontinuation of the causative drug. Irreversible or progressive DIP has been considered as an indication of presymptomatic parkinsonian deficit, unmasked but not caused by the offending drug, but it could be explained by persistent toxicity of the responsible pharmacological agents on the nigrostriatal dopamine pathway. The best treatment of DIP is prevention, including the avoidance of prescription of causative drugs whenever it is not strictly necessary. In patients who require potentially risky medication, it is necessary to perform adequate monitoring for early parkinsonian deficits and early discontinuation if these deficits appear. Atypical neuroleptics are associated with lower risk than first generation antipsychotic drugs. Special precautions are needed in elderly subjects, in patients treated with multiple drugs for prolonged periods of time and in those with familial risk factors including familial parkinsonism or tremor, or in those with genetic variants of genes involved in idiopathic Parkinson's disease.