Neuronal calcium homeostasis

NMDA receptor, with less susceptibility to Ca2+ mediated entry by glutamate [129, 130], 

In total, antagonizing direct upstream control over the nNOS isoform can be achieved in part by application of internal and external Ca2+ channel blockers, Ca2+ buffering agents, hyperpolarizing agents or selective nNOS inhibitors such as 6 or 7-nitroindazole, l-(2-trifluoromethylphenyl) imidazole or 6-phenyl-2-aminopyridines [131-133], 

---

While cyanide inhibition of cytochrome c oxidase may not account for the full spectrum of toxicity in CS exposure, cyanide toxicity may include an array of biochemical interactions (Way, 1984). These include lipid peroxidation (Johnson et al, 1987), cyanide release of endogenous opioids to cause respiratory paralysis (Leung et al, 1986), disruption of neuronal calcium homeostasis (Johnson et al, 1986), and phospholipids hydrolysis (Sakaida and Farber,... 

Mitochondrial dysfnnction during seizures can also alter neuronal excitability. The inhibition of the mitochondrial respiratory chain enzymes, such as cytochrome c oxidase and snccinate dehydrogenase, evokes seizures. This may be due to an intracellular decrease in ATP levels and alterations in neuronal calcium homeostasis (Kunz, 2002). Alternatively, free radicals may attack mitochondria, inhibit the activity of the respiratory chain and induce a transient permeability. This results in a decline of ATP production and excessive release of free radicals, consequently causing cell death (Arzimanoglou et al, 2002). 

It has been hypothesized that the mechanisms whereby mefloquine increases the risk of seizures in patients with a history of seizures, which may be via altered neuronal calcium homeostasis, altered gap-junction functioning, and neuronal cell death, are particularly associated with a mutation in EPMl, a gene that is associated with progressive myoclonic epilepsy type 1, and hence altered GABA activity [10 ]. The author proposed that mefloquine should be contraindicated in people with the EPMl mutation and in those with a history of myoclonus or ataxia, or a family history of degenerative neurological disorders that are consistent with the presence of the EPMl mutation. 

Stimulation of the neuron lea ding to electrical activation of the nerve terminal in a physiologically relevant manner should eUcit a calcium-dependent release of the neurotransmitter. Although release is dependent on extracellular calcium, intracellular calcium homeostasis may also modulate the process. Neurotransmitter release that is independent of extracellular calcium is usually artifactual, or in some cases may represent release from a non-neuronal sources such as gha (3). 

Bonavia R, Bajetto A, Barbero S, Albini A, Noonan DM, Schettini G (2001) HlV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons. Biochem Biophys Res Commun 288 301-308... 

Abnormal neuronal calcium and sodium activity and homeostasis cause neurotransmitter dysreguiation. 

Figure 2. Mechanisms and signalings of neuronal death. Death can be initiated at the membrane by activation of death domain receptors (DDR), or by intracellular signalings through oxidative stress (and the production of reactive oxigen species, ROS), perturbed calcium homeostasis, mitochondrial dysfunction (release of cytochrome c, cytC), activation of caspases, as well as reactivation of cell cycle genes such as the transcription factor E2F (see text). Interconnections have been demonstrated (dotted lines) depending on the apoptotic context...

The PA4 peptide and an excessive amount of APP have proved to be neurotoxic. The accumulation of the pA4 peptide between synapses may be responsible for neuronal dysfunction and death (Schubert et al. 1991). PA4 could also modify the N-methyl-D-aspartate (NMDA) receptor, making possible the presence of neurotoxicity via the excitotoxin and calcium pathways [Mattson et al. 1992). Drugs that interfere with these pathways or alter calcium homeostasis have a potential therapeutic role. 

Mathur C, Prasad WK, Raju VS, et al Steroids and their conjugates in the mammalian brain. Proc Natl Acad Sci USA 90 85-88, 1993 Mattes JA A pilot study of combined trazodone and tryptophan in obsessive-compulsive disorder. Int Clin Psychopharmacol 1 170-173, 1986 Mattson MP, Cheng B, Davis D, et al Beta-amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 12 376-389, 1992... 

In a series of studies, Dubovsky et al. ( 34) measured intracellular calcium ion concentrations in bipolar manic and depressed patients. They found decreases in mean concentrations in four bipolar, manic, and five bipolar, depressed, patients, in comparison with seven normothymic subjects without personal or first-degree relative histories of psychiatric disorders. Their findings were consistent with a diffuse abnormality in the mechanisms modulating intracellular calcium homeostasis. Further, this phenomenon s presence in both platelets and lymphocytes lends credence to a disruption in the cell membrane, the G-protein, or other mechanisms involved in the homeostasis of intracellular calcium ion concentrations. This may also support an extension of their findings from peripheral to neuronal tissue. 

Local anesthetics have poorly understood effects on inflammation at sites of injury, and these anti-inflammatory effects may contribute to improved pain control in some chronic pain syndromes. At the concentrations used in spinal anesthesia, local anesthetics can inhibit transmission via substance P (neurokinin-1), NMDA, and AMPA receptors in the secondary afferent neurons (Figure 26-1). These effects may contribute to the analgesia achieved by subarachnoid administration. Local anesthetics can also be shown to block a variety of other ion channels, including nicotinic acetylcholine channels in the spinal cord. However, there is no convincing evidence that this mechanism is important in the acute clinical effects of these drugs. High concentrations of local anesthetics in the subarachnoid space can interfere with intra-axonal transport and calcium homeostasis, contributing to potential spinal toxicity. 

---