Benefit of tianeptine and morphine in a transgenic model of familial amyotrophic lateral sclerosis

Abstract

The familial form of amyotrophic lateral sclerosis (FALS) has been linked in some cases to dominant mutations in the gene encoding the Cu/Zn superoxide dismutase (SOD1) mutation. Transgenic mice bearing the G93A SOD1 mutation develop clinical symptoms and pathological features similar to those described in the human disease and represent a good model to explore the potential benefit of therapeutic agents. Using this animal model, we tested the efficacy of morphine and tianeptine treatments, separately and in association, on both disease progression and survival. Acute injection of either of them, administered daily and before the onset of the disease, significantly prolonged the survival of the transgenic mice.

One Universal Common Endpoint in Mouse Models of Amyotrophic Lateral Sclerosis

“…Moreover, the time used to establish the righting reflex is not standardized (at least 3 s), introducing a confounding within the righting reflex methodology. Some studies did not specify the length of time used as the cutoff for the righting reflex [26], [54], [60], [73], [78], [85], [90], [93].…”

“…Different laboratories using mouse models of ALS have chosen varying endpoints, some reflecting more advanced stages of the disease, including the righting reflex (mice are placed on their sides and are euthanized if they cannot right themselves to sternum in 3–30 s, time chosen depends on the laboratory), an inability to splay the hindlimbs due to paralysis, a percentage decrease in motor performance or grip strength from initial values, an inability to obtain food or water, a defined percentage of body weight loss from peak weight, serious eye infection, an inability to self-groom, no spontaneous breathing or movement for a predetermined time with no response to pain, complete hindlimb paralysis, or combinations of two or more of these criteria. The most commonly used endpoint is a righting reflex of at least 3 s [1], [4], [5], [7], [10]–[15], [17]–[23], [25], [27], [28], [30]–[32], [36], [38]–[47], [49]–[51], [53], [57]–[59], [61], [62], [64], [65], [68], [70]–[72], [74], [77], [79]–[83], [84], [86]–[89], [91], [94]–[97], however some studies did not specify the length of time used as the cutoff for the righting reflex [26], [54], [60], [73], [78], [85], [90], [93]. The popularity of the righting reflex is possibly due to its relative simplicity, value as an indicator of proprioception deterioration [102], [103], and/or history as the first endpoint used in an intervention study in this particular disease model …”

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

“…Moreover, our group has demonstrated that administration of LK-ethyl ester slows disease progression in the SOD1 G93A mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) [67,68] in which, incidentally, prognosis is also beneficially affected by tianeptine [70]. These in vivo findings begin to validate the potential of LK derivatives as novel pharmacophores for therapeutic intervention against certain neurodegenerative disorders.…”

Exogenous Delivery of Heat Shock Protein 70 Increases Lifespan in a Mouse Model of Amyotrophic Lateral Sclerosis

“…In the G93A SOD1 mouse, hindlimb tremor and weakness is observed at ϳP90 with death occurring at ϳP120 (Gurney et al, 1996). Other studies have begun experimental treatments in these animals at or approximately at P50 (Gurney et al, 1996;Li et al, 2000;Canton et al, 2001;Azari et al, 2003;Kaspar et al, 2003;Azari et al, 2005;Schutz et al, 2005;Chritin et al, 2006). For this study, treatment and behavioral analysis were started at P50.…”