An experimental model based on kainic acid (KA) injections replicates many phenomenological features of human temporal lobe epilepsy, the most common type of epilepsy in adults. Taurine, 2-aminoethanesulfonic acid, present in high concentrations in many invertebrate and vertebrate systems, is believed to serve several important biological functions. In addition, it is believed to have a neuroprotective role against several diseases. In the present study, an experimental mouse model based on taurine pretreatment prior to KA administration has been improved to study whether taurine has a neuroprotective effect against KA-induced behavior and cell damage. Under different treatments tested, taurine's most neuroprotective effects were observed with intraperitoneal taurine injection (150 mg/kg dosage) 12 hr before KA administration. Thus, a reduction in or total absence of seizures, together with a reduction in or even disappearance of cellular and molecular KA-derived effects, was detected in mice pretreated with taurine compared with those treated only with KA. Moreover, the use of tritiated taurine revealed taurine entry into the brain, suggesting possible changes in intracellular:extracellular taurine ratios and the triggering of pathways related to neuroprotective effects.

Taurine is one of the most abundant free amino acids in the mammalian central nervous system, where it is crucial to proper development. Moreover, taurine acts as a neuroprotectant in various diseases; in epilepsy, for example, it has the capacity to reduce or abolish seizures. In the present study, taurine levels has been determine in mice treated with Kainic Acid (KA) and results showed an increase of this amino acid in hippocampus but not in whole brain after 3 and 7 days of KA treatment. This increase occurs when gliosis was observed. Moreover, taurine transporter (TAUT) was found in astrocytes 3 and 7 days after KA treatment, together with an increase in cysteine sulfinic acid decarboxylase (csd) mRNA, that codifies for the rate-limiting enzyme of taurine synthesis, in the hippocampus at the same times after KA treatment. Glial cultures enriched in astrocytes were developed to demonstrate that these cells are responsible for changes in taurine levels after an injury to the brain. The cultures were treated with proinflammatory cytokines to reproduce gliosis. In this experimental model, an increase in the immunoreactivity of GFAP was observed, together with an increase in CSD and taurine levels. Moreover, an alteration in the taurine uptake-release kinetics was detected in glial cells treated with cytokine. All data obtained indicate that astrocytes could play a key role in taurine level changes induced by neuronal damage. More studies are, therefore, needed to clarify the role taurine has in relation to neuronal death and repair.

Taurine, 2-aminoethanesulfonic acid, is present at high concentrations in many invertebrate and vertebrate systems and has several biological functions. In addition, it has been related to a neuroprotective role against several diseases such as epilepsy. In the present work, we treated mice with taurine and examined its effects on the expression of proteins in the hippocampus associated with calcium regulation. Taurine treatment alters the presence of calbindin-D28k, calretinin, and parvalbumin in the brain, mainly in the hippocampus. It also reduced CaMKII activity, indicating that taurine could alter calcium signaling pathways. However, the activity of calpain, a protease related to apoptosis induced by calcium signalling, did not change. The concentration of taurine in the hippocampus was also unaffected by the treatment. These results provide new insight into the role of taurine in calcium homeostasis.

Dithiocarbamates (DTCs), such as disulfiram, have been used in aversion therapy for alcoholism even though an inherent toxicity is induced, which is related mainly to peripheral neuropathy and is associated with behavioural and neurological complications. At anatomical and histopathological levels, DTCs affect structural elements in nervous tissue, such as axonal degeneration and alterations in the cytoskeletal proteins of astrocytes. Therefore, given the axonal effects of DTCs and to gain further insight into axonal growth and axonal pathfinding in the central nervous system (CNS), here we established an in vivo experimental model of mouse development. Daily intraperitoneal injections of N,N-diethyldithiocarbamate (DEDTC), the first metabolite of disulfiram, were given from postnatal day 2 (P2) until P15. From P16 until P30, animals were not treated. Treatment induced considerable physiological alterations, such as growth delay, throughout postnatal development. Moreover, by immunohistochemistry techniques, we observed important alterations in the cytoskeletal glial protein at early stages of postnatal development. At later stages (P15), the immunoreactivity pattern detected by an antibody against axonal neurofilaments (anti-NF-H) showed alteration in the axonal distribution pattern followed by drastic axonal loss at P22, data that were corroborated using an anti-MBP (myelin basic protein) antibody. Using an antibody against the beta amyloid precursor protein (APP), we detected axonal injury. Furthermore, given that we observed axonal re-growth in adulthood in the in vivo model presented, we propose that this model would be a good system in which to identify new strategies for inducing regenerative growth in neural diseases in which axonal regeneration is blocked.

Axonal degeneration has been described as the pathological hallmark of peripheral neuropathies induced by DEDTC. In addition, axonal damage has also been observed in the brain of mice treated daily with DEDTC along postnatal development, though with this experimental model there was observed to be axonal recovery after treatment, during the adulthood. To focus on this axonal dynamic activity, damage-recovery, a key axonal protein, the microtubule associated protein tau, was analyzed in this DEDTC model. Tau is a phosphoprotein and its dynamic site-specific phosphorylation is essential for its proper function; in fact, high levels are correlated with cell dysfunction. Furthermore, the levels of tau phosphorylation are associated with dynamic microtubules during periods of high plasticity. Thus, phosphorylated tau at two sites of phosphorylation, Ser(199) and Ser(396), were evaluated during the second week of postnatal development and throughout adulthood. The results obtained by Western blot made it evident that the levels of p-tau Ser(199) and p-tau Ser(396) were higher in treated mice than in controls. Interestingly, by immunohistochemistry there was shown to be an increase in p-tau-immunolabeling in neuronal soma together with axonal tract alterations in treated animals with respect to controls, and the analyses of GSK3 beta and cdk5 revealed an increase in its activity in DEDTC-treated animals. Nevertheless, in the adult a general decline in p-tau was observed together with a rescue of axonal tract. All these data support the idea that the axonal damage induced by DEDTC treatment along postnatal development is followed by an axonal rescue during adulthood.

Our data suggest that DEDTC provokes alterations in biogenic amines and in different substrates of neurotransmitter systems, which could explain some of the neurobehavioural effects observed in patients treated with disulphiram.

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Taurine, 2-aminoethanesulfonic acid, is present at high concentrations in many invertebrate and vertebrate systems, and it has several biological functions. In addition, it has been related to a neuroprotective role against several diseases, such as epilepsy. It has been reported that taurine induces a decrease of calbindin-D28k, calretinin, and parvalbumin protein levels in the hippocampus 3 days after administration. In the present work we hypothesized that the decrease of these proteins could alter the action of kainic acid (KA) and make mice more susceptible to excitotoxicity. Therefore, we treated mice with taurine and after 3 days treated them with KA. The results showed that taurine pretreatment did not induce a major susceptibility to KA. Moreover, neurodegeneration was reduced in pretreated mice. However, astrogliosis was similar to that observed in mice treated only with KA. The immunohistochemistries for calbindin-D28k, calretinin, and parvalbumin showed that these proteins were reduced as a consequence of KA treatment and of taurine treatment. However, mice pretreated with taurine prior to KA administration presented the same reduction in these proteins as mice treated with only taurine or only KA.