322,999 research outputs found
Autophagy activation in glutamate-induced motor neuron loss
No full textRecent literature demonstrated that exposure to excitatory amino acid in specific experimental conditions might produce a defect in the autophagy pathway. Such an effect was observed in motor neurons exposed chronically to glutamate agonists. On the other hand, it is well known that glutamate induces motor neuron death and this is supposed to play a key role in the physiopathology of motor neuron loss in amyotrophic lateral sclerosis (ALS). Similarly, a defective recruitment of autophagy was recently documented in ALS. In the present study we found that exposure of motor neurons to kainic acid produces intracellular changes associated with defective autophagy. In this experimental conditions, pharmacological activation of autophagy rescues the loss of motor neurons
A2A receptors and methamphetamine toxicity: a role of adenosine as an endogenous neurotoxin
No full textAdenosine A2A are a class of purinergic receptors largely expressed in dopamine (DA)-rich areas of the central nervous system. In particular, they are abundant within basal ganglia, where they modulate the activity of various neurotransmitters, including DA. Despite the lack of knowledge on their fine physiological mechanisms, it is worth to mention that A2A antagonists prevent neuronal death and dyskinesia in Parkinsonism. Moreover the neuroprotective effects observed after blockade of adenosine A2A receptors in several models of neurotoxicity suggests a toxic effect for endogenous adenosine In the light of these evidences, in the present study, by using in vitro models of DA neurons, we investigated: (i) whether A2A antagonists protect DA containing neurons against methamphetamine (METH); (ii) whether activation of A2A receptors produce neurodegeneration. This was done either using A2A agonist receptor NECA or the endogenous compound adenosine; (iii) whether specific cell mechanisms are involved in these phenomena. We found that A2A antagonists protect DA cells against METH neurotoxicity. Moreover, we found that NECA and adenosine both produced a toxic effects. In the light of the key role of autophagy in modulating the survival of DA neurons we found that A2A antagonists increase, while A2A agonists decrease, autophagy. These results suggest that neuroprotection induced by A2A antagonists may be mediated by enhancement of autophagy. As expected we found that pre-treatment with a non-adenosine related inducer of autophagy produced the same protective effects obtained with A2A antagonists. Our data indicate for the first time, that A2A antagonists are protective in DA neurons against METH. Such an effect appear to be mediated by the enhancement of autophagy. On the other hand we found that activation of A2A receptor produces neurotoxicity. Interestingly these effects was reproduced by administering endogenous adenosine. This suggests that adenosine may produce neurodegeneration by inhibiting the autophagy pathway
Parkinson’s disease and the gut: a well known clinical association in need of an effective cure and explanation
No full textParkinson's disease (PD) is a neurodegenerative disorder which leads to severe movement impairment; however, Parkinsonian patients frequently suffer from gastrointestinal (GI) problems which at present are poorly understood, scarcely investigated, and lack an effective cure. Traditionally, PD is attributed to the loss of mesencephalic dopamine-containing neurons; nonetheless, additional nuclei, such as the dorsal motor nucleus of the vagus nerve and specific central noradrenergic nuclei, are now identified as targets of PD. While the effects of PD on the somatic motor systems are well characterized, the influence on the digestive system still needs to be clarified. Recent findings demonstrate the occurrence of pathological alterations within peripheral neuronal networks in the GI tract of Parkinsonian patients. However, it remains unclear whether a real cell loss occurs, and whether this happens specifically for a subclass of autonomic neurons or if it reflects the sole loss of autonomic nerves. This review summarizes the neurochemical and morphological changes which might be responsible for impaired GI motility. Moreover, we focus on the experimental models to reproduce the altered digestive system of Parkinsonian patients since an experimental model able to mimic such features of PD is required. In the last part of the manuscript, we suggest potential therapeutic targets
“New Pyridazinones: Synthesis and Correlation Between Structure and α-Blocking Activity”.
No full textThe "Parkinsonian heart": from novel vistas to advanced therapeutic approaches in Parkinson's disease
No full textThe present manuscript reviews novel data on the progressive involvement of different regions of the central nervous system as well as peripheral nerves in Parkinson's disease. Most of these regions are involved in the regulation of the autonomic nervous system, and their damage is concomitant with the specific loss of sympathetic cardiac axon terminals. This causes a cardiovascular dysfunction, which occurs solely in Parkinsonian patients. In order to specify the peculiarity of this cardiovascular alteration we coined the term "Parkinsonian Heart". This is characterized by a severe loss of the physiological noradrenergic innervation and a slight impairment of central autonomic control and it is often characterized by drug-induced morpho-functional alterations. In fact, the current dopamine substitution therapy could make worse such an already abnormal heart. For instance, structure-activity studies on dopamine substitutive drugs report that dopamine agonists belonging to the class of ergot derivatives may produce, with a high frequency, valvular fibrosis in Parkinsonian patients. These effects recently became a major issue and led to consider all ergot dopamine agonists as dangerous for the treatment of Parkinson's disease. In the present review we re-describe the effects of dopamine agonist within the specific context of the Parkinsonian heart. In line with this, additional factors need to be considered: 1--The lack of noradrenergic innervation which might play a significant role in the fibrogenic mechanism. 2--The ergot structure per se, which is not sufficient, but it is rather the ability to act as agonist at 5HT(2B) or alpha-noradrenergic receptors to determine the fibrotic reaction. Therefore, we suggest that binding to these receptor subtypes, joined with the lack of endogenous noradrenergic innervation, might synergize to produce the cardiac fibrosis
Affinity profiles at five cloned human muscarinic receptors (m1-m5) of a new series of antimuscarinic drugs.
No full text“Novel and Highly Selective Postsynaptic α-Adrenoreceptor Antagonists: Synthesis and Structure-Activity Relationships of Alkane-Bridged [4-(phenoxyethyl)-1-piperazinyl]-3 (2H)-pyridazinones”.
No full textPathways of methamphetamine toxicity
No full textMethamphetamine (METH) is a drug of abuse which is neurotoxic for the nigrostriatal system. METH-induced neurodegeneration involves production of reactive oxygen species, triggering autophagic vacuoles within nigral neurons of chronic abusers of METH. In fact, Cu,Zn-superoxide dismutase 1 (SOD1) is a critical protein for the neurotoxic effects of METH on DA neurons. Moreover, mutations in the SOD1 gene cause amyotrophic lateral sclerosis, a dramatic neurodegenerative disorder. In the present paper we demonstrate that in G93A transgenic mice, overexpressing the ALS-linked mutant form of SOD1, surviving motor neurons share common intracellular alterations with METH-exposed DA neurons. We hypothesize that in mutant SOD1 transgenic mice, a defective autophagy might be responsible for the neurotoxic effects seen with in nigral neurons during METH toxicity
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