Search PubMed⌕ Search

Biomedical subjects

David Blum

Publications and source records attributed to David Blum.

28 records · Page 2Linked to original sources
PubMed2003

A dual role of adenosine A2A receptors in 3-nitropropionic acid-induced striatal lesions: implications for the neuroprotective potential of A2A antagonists.

Reduction of A2A receptor expression is one of the earliest events occurring in both Huntington's disease (HD) patients and mice overexpressing the N-terminal part of mutated huntingtin. Interestingly, increased activity of A2A receptors has been found in striatal cells prone to degenerate in experimental models of this neurodegenerative disease. However, the role of A2A receptors in the pathogenesis of HD remains obscure. In the present study, using A2A-/- mice and pharmacological compounds in rat, we demonstrate that striatal neurodegeneration induced by the mitochondrial toxin 3-nitropropionic acid (3NP) is regulated by A2A receptors. Our results show that the striatal outcome induced by 3NP depends on a balance between the deleterious activity of presynaptic A2A receptors and the protective activity of postsynaptic A2A receptors. Moreover, microdialysis data demonstrate that this balance is anatomically determined, because the A2A presynaptic control on striatal glutamate release is absent within the posterior striatum. Therefore, because blockade of A2A receptors has differential effects on striatal cell death in vivo depending on its ability to modulate presynaptic over postsynaptic receptor activity, therapeutic use of A2A antagonists in Huntington's as well as in other neurodegenerative diseases could exhibit undesirable biphasic neuroprotective-neurotoxic effects.

Adenosine↗
PubMed2003

The influence of comorbid depression on quality of life for people with epilepsy.

The impact of depression on health-related quality of life (HRQOL) for people with epilepsy was evaluated using a postal survey that assessed HRQOL, depression, and seizure severity (N=501). QOLIE-89 scores were significantly reduced by comorbid depression (all P<0.0001) for all types of seizures. People with predominantly major, partial, and minor seizures had significantly poorer HRQOL if they had mild-moderate or major depression (all P<0.0001). People with any type of recent seizure had significantly poorer HRQOL in all domains than people who were seizure-free for 3 months. Differences between groups by depression category were clinically significant (>12 points). Depression (r=-0.72), seizure bothersomeness (r=-0.54), seizure severity (r=-0.37), and days disabled with seizures (r=-0.65) were significantly correlated with poorer HRQOL in all domains than found for nondepressed patients (all subscales P<0.0001). Clinical depression is significantly associated with poorer HRQOL among people with all types of seizures.

Adult↗
PubMed2003

Adenosine receptors and Huntington's disease: implications for pathogenesis and therapeutics.

Huntington's disease (HD) is a devastating hereditary neurodegenerative disorder, the progression of which cannot be prevented by any neuroprotective approach, despite major advances in the understanding of its pathogenesis. The study of several animal models of the disease has led to the discovery of both loss-of-normal and gain-of-toxic functions of the mutated huntingtin protein and the elucidation of the mechanisms that underlie the formation of huntingtin aggregates and nuclear inclusions. Moreover, these models also provide good evidence of a role for excitotoxicity and mitochondrial metabolic impairments in striatal neuronal death. Adenosine has neuroprotective potential in both acute and chronic neurological disorders such as stroke or Parkinson's disease. Here we review experimental data on the role of A1 and A2A adenosine receptors in HD that warrant further investigation of the beneficial effects of A1 agonists and A2A antagonists in animal models of HD. Future pharmacological analysis of adenosine receptors could justify the use of A1 agonists and A2A antagonists for the treatment of HDin clinical trials.

Adenosine↗
PubMed2003

The influence of comorbid depression on seizure severity.

PURPOSE: To determine the relation between depressive symptoms and seizure severity among people with epilepsy. METHODS: A postal questionnaire was used to survey a nationwide community sample about seizures and depression. The Seizure Severity Questionnaire (SSQ) assessed the severity and bothersomeness of seizure components. The Centers for Epidemiological Studies-Depression scale categorized levels of depression. RESULTS: Respondents categorized as having current severe (SEV, n = 166), mild-moderate (MOD, n = 74), or no depression (NO, n = 443) differed significantly in SSQ scores (all p < 0.0001). People with SEV or MOD reported significantly worse problems than did those with NO depression for overall seizure recovery (mean, 5.3, 4.9, 4.5, respectively); overall severity (5.0, 4.5, 4.2); and overall seizure bother (5.3, 4.8, 4.4) (all p < 0.005). Cognitive, emotional, and physical aspects of seizure recovery also were rated worse among people with SEV than with NO depression (all p < 0.05). Symptoms of depression were significantly correlated with higher levels of all components of generalized tonic-clonic seizure severity (r = 0.33-0.48; all p < 0.0001), and partial seizures (r = 0.31-0.38; all p < 0.01). CONCLUSIONS: Clinically depressed people with epilepsy reported higher levels of perceived severity and bother from seizures, as well as greater problems with overall seizure recovery than did nondepressed people experiencing similar types of seizures. The pervasive influence of depressive symptoms on reports of seizure activity suggests that people with epilepsy should be screened for depression. These data highlight the importance of detecting and treating depression among people with epilepsy.

Adult↗
PubMed2002

The adenosine A1 receptor agonist adenosine amine congener exerts a neuroprotective effect against the development of striatal lesions and motor impairments in the 3-nitropropionic acid model of neurotoxicity.

Huntington's disease is a genetic neurodegenerative disorder characterized clinically by both motor and cognitive impairments and striatal lesions. At present, there are no pharmacological treatments able to prevent or slow its development. In the present study, we report the neuroprotective effect of adenosine amine congener (ADAC), a specific A1 receptor agonist known to be devoid of any of the side effects that usually impair the clinical use of such compounds. Remarkably, in a rat model of Huntington's disease generated by subcutaneous infusion of the mitochondrial inhibitor 3-nitropropionic acid (3NP), we have observed that an acute treatment with ADAC (100 microg x kg(-1) x d(-1)) not only strongly reduces the size of the striatal lesion (-40%) and the remaining ongoing striatal degeneration (-30%), but also prevents the development of severe dystonia of hindlimbs. Electrophysiological recording on corticostriatal brain slices demonstrated that ADAC strongly decreases the field EPSP amplitude by 70%, whereas it has no protective effect up to 1 microm against the 3NP-induced neuronal death in primary striatal cultures. This suggests that ADAC protective effects may be mediated presynaptically by the modulation of the energetic impairment-induced striatal excitotoxicity. Altogether, our results indicate that A1 receptor agonists deserve further experimental evaluation in animal models of Huntington's disease.

Adenosine↗
PubMed2002

Clearance of manganese from the rat substantia nigra following intra-nigral microinjections.

Chronic exposure to manganese (Mn) positively correlates with the occurrence of Parkinsonism but little is known about mechanisms of its neurotoxicity. In the present study, we determined the clearance of Mn from rat substantia nigra after its nigral injection and correlated it with the establishment of apomorphine-induced rotational behaviour and loss of striatal tyrosine hydroxylase (TH) immunoreactivity. Our results suggest that Mn is slowly cleared from the substantia nigra, following a first-order kinetics with a t(1/2) of 3 days. Appearance of apomorphine-induced rotational behaviour and loss of TH immunoreactivity within the striatum follows metal clearance were both detected 24 hours after intra-nigral Mn microinjection and maximal 72 hours after injection. The present data suggest that the cellular mechanisms induced by Mn and leading to dopaminergic cell death, occurred shortly after its injection and that the metal concentration needs to reach a threshold value to induce neurotoxic effects. This would indicate that nigral damages are a direct consequence of Mn accumulation.

Animals↗
PubMed2002

Striatal and cortical neurochemical changes induced by chronic metabolic compromise in the 3-nitropropionic model of Huntington's disease.

In the present study, we aimed to determine the time-course of neurochemical changes occurring following metabolic impairments produced by 3-nitropropionic (3NP) acid in a rat model of Huntington's disease. We found that the occurrence of striatal lesions was accompanied by (1) strong transcriptional alterations within the degenerative lateral striatum, (2) receptor upregulations within the preserved medial striatum, and (3) transcriptional increases within the unaltered cerebral cortex. These phenomena were preceded by transcriptional modifications in striatal subareas prone to degeneration even before the lesion was visible but not in the overlying cortex, known to be spared in this model. Of great interest, the density of A(2A) receptor binding sites, located on striato-pallidal neurons, was (1) downregulated at the time of worsening of symptoms and (2) strongly upregulated within the spared medial striatum after the lesion occurrence. This study therefore highlights the differential neurochemical responses produced by 3NP depending on the fate of the metabolically inhibited area and strongly suggests the involvement of A(2A) receptors in the development of striatal pathology under metabolic compromise.

Animals↗
PubMed2001

Decline in Verbal Memory Associated with Duration of Epilepsy: An Intracarotid Amobarbital Study.

Background. Many patients with mesial temporal sclerosis (MTS) observe that their memory has declined over time, but objective evidence for this is scant.Method. Verbal memory scores were obtained during amobarbital injection of the right carotid artery in 30 right-handed patients with right mesial temporal sclerosis and unilateral right temporal lobe seizures. These were compared with duration of epilepsy and seizure frequency. An estimate of the total number of lifetime seizures was formed by multiplying epilepsy duration by seizure frequency.Results. Verbal memory function in the left temporal lobe was negatively associated with longer duration of epilepsy (P < 0.05). There was a strong negative correlation between verbal memory and increased lifetime number of seizures (P < 0.01).Conclusion. This study provides evidence that seizures arising in the right temporal lobe lead to progressive dysfunction of memory functions in the contralateral side.

Journal Article↗