5-HTP
5-hydroxytryptophan
Here, information will be collected relevant to the use of 5-HTP as an ALS therapeutic.
Role of serotonin in ALS
Platelet serotonin is decreased in PALS and its level correlates with survival (but not disease duration):
Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters. [1]
However, in end-stage SOD1 rats depletion of serotonin did not affect preservation of the respiratory function:
Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: (1) serotonin depletion with parachlorophenylalanine (PCPA), (2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, (3) NADPH oxidase inhibition (apocynin), and (4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. [3]
Serotonin syndrome
[1]<bibtex> @article{Dupuis2010, abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease involving upper and lower motor neurons loss. Clinical features are highly variable among patients and there are currently few known disease-modifying factors underlying this heterogeneity. Serotonin is involved in a range of functions altered in ALS, including motor neuron excitability and energy metabolism. However, whether serotoninergic activity represents a disease modifier of ALS natural history remains unknown.
METHODOLOGY: Platelet and plasma unconjugated concentrations of serotonin and plasma 5-HIAA, the major serotonin metabolite, levels were measured using HPLC with coulometric detection in a cohort of 85 patients with ALS all followed-up until death and compared to a control group of 29 subjects.
PRINCIPAL FINDINGS: Platelet serotonin levels were significantly decreased in ALS patients. Platelet serotonin levels did not correlate with disease duration but were positively correlated with survival of the patients. Univariate Cox model analysis showed a 57\% decreased risk of death for patients with platelet serotonin levels in the normal range relative to patients with abnormally low platelet serotonin (p = 0.0195). This protective effect remained significant after adjustment with age, gender or site of onset in multivariate analysis. Plasma unconjugated serotonin and 5-HIAA levels were unchanged in ALS patients compared to controls and did not correlate with clinical parameters.
CONCLUSIONS/SIGNIFICANCE: The positive correlation between platelet serotonin levels and survival strongly suggests that serotonin influences the course of ALS disease.}, author = {Dupuis, Luc and Spreux-Varoquaux, Odile and Bensimon, Gilbert and Jullien, Philippe and Lacomblez, Lucette and Salachas, Fran\c{c}ois and Bruneteau, Ga\"{e}lle and Pradat, Pierre-Fran\c{c}ois and Loeffler, Jean-Philippe and Meininger, Vincent}, doi = {10.1371/journal.pone.0013346}, editor = {Egles, Christophe}, file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Dupuis et al. - 2010 - Platelet Serotonin Level Predicts Survival in Amyotrophic Lateral Sclerosis.pdf:pdf}, issn = {1932-6203}, journal = {PLoS ONE}, keywords = {Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: blood,Blood Platelets,Blood Platelets: metabolism,Case-Control Studies,Chromatography, High Pressure Liquid,Cohort Studies,Humans,Hydroxyindoleacetic Acid,Hydroxyindoleacetic Acid: blood,Serotonin,Serotonin: blood,Survival Analysis}, month = oct, number = {10}, pages = {e13346}, pmid = {20967129}, title = Template:Platelet Serotonin Level Predicts Survival in Amyotrophic Lateral Sclerosis, url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2954194\&tool=pmcentrez\&rendertype=abstract}, volume = {5}, year = {2010} } </bibtex>
[2]<bibtex> @article{Koschnitzky2014, abstract = {Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5-11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1(G93A) and control: nontransgenic and SOD1(WT)) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1(G93A) mice reached end stage ∼8 days (∼6\% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models.}, author = {Koschnitzky, J E and Quinlan, K A and Lukas, T J and Kajtaz, E and Kocevar, E J and Mayers, W F and Siddique, T and Heckman, C J}, doi = {10.1152/jn.00425.2013}, issn = {1522-1598}, journal = {Journal of neurophysiology}, keywords = {Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: diagnosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Antidepressive Agents, Second-Generation,Antidepressive Agents, Second-Generation: administ,Behavior, Animal,Behavior, Animal: drug effects,Disease Models, Animal,Disease Progression,Dose-Response Relationship, Drug,Fluoxetine,Fluoxetine: administration \& dosage,Longitudinal Studies,Mice,Mice, Transgenic,Rotarod Performance Test,Serotonin Uptake Inhibitors,Serotonin Uptake Inhibitors: administration \& dosa,Treatment Outcome,Tremor,Tremor: diagnosis,Tremor: physiopathology,Tremor: prevention \& control}, month = jun, number = {11}, pages = {2164--76}, pmid = {24598527}, title = Template:Effect of fluoxetine on disease progression in a mouse model of ALS., url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4097867\&tool=pmcentrez\&rendertype=abstract}, volume = {111}, year = {2014} } </bibtex>
[3]<bibtex> @article{Nichols2014, abstract = {In rats over-expressing SOD1G93A, ventilation is preserved despite significant loss of respiratory motor neurons. Thus, unknown forms of compensatory respiratory plasticity may offset respiratory motor neuron cell death. Although mechanisms of such compensation are unknown, other models of respiratory motor plasticity may provide a conceptual guide. Multiple cellular mechanisms give rise to phrenic motor facilitation; one mechanism requires spinal serotonin receptor and NADPH oxidase activity whereas another requires spinal adenosine receptor activation. Here, we studied whether these mechanisms contribute to compensatory respiratory plasticity in SOD1G93A rats. Using plethysmography, we assessed ventilation in end-stage SOD1G93A rats after: (1) serotonin depletion with parachlorophenylalanine (PCPA), (2) serotonin (methysergide) and A2A (MSX-3) receptor inhibition, (3) NADPH oxidase inhibition (apocynin), and (4) combined treatments. The ability to increase ventilation was not decreased by individual or combined treatments; thus, these mechanisms do not maintain breathing capacity at end-stage motor neuron disease. Possible mechanisms giving rise to enhanced breathing capacity with combined treatment in end-stage SOD1G93A rats are discussed.}, author = {Nichols, N L and Johnson, R A and Satriotomo, I and Mitchell, G S}, doi = {10.1016/j.resp.2014.03.005}, file = {:C$\backslash$:/Users/riku/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Nichols et al. - 2014 - Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats.pdf:pdf}, issn = {1878-1519}, journal = {Respiratory physiology \& neurobiology}, keywords = {Acetophenones,Acetophenones: pharmacology,Adenosine,Adenosine A2 Receptor Antagonists,Adenosine A2 Receptor Antagonists: pharmacology,Adenosine: physiology,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: drug therapy,Amyotrophic Lateral Sclerosis: pathology,Amyotrophic Lateral Sclerosis: physiopathology,Animals,Enzyme Inhibitors,Enzyme Inhibitors: pharmacology,Humans,Male,Methysergide,Methysergide: pharmacology,Motor Neurons,Motor Neurons: drug effects,Motor Neurons: pathology,Motor Neurons: physiology,NADPH Oxidase,NADPH Oxidase: antagonists \& inhibitors,NADPH Oxidase: metabolism,Phrenic Nerve,Phrenic Nerve: drug effects,Phrenic Nerve: pathology,Phrenic Nerve: physiopathology,Plethysmography,Pulmonary Ventilation,Pulmonary Ventilation: drug effects,Pulmonary Ventilation: physiology,Rats, Sprague-Dawley,Rats, Transgenic,Respiration,Respiration: drug effects,Serotonin,Serotonin Antagonists,Serotonin Antagonists: pharmacology,Serotonin: physiology,Superoxide Dismutase,Superoxide Dismutase: genetics,Superoxide Dismutase: metabolism,Tidal Volume,Tidal Volume: drug effects,Tidal Volume: physiology,Xanthines,Xanthines: pharmacology}, month = jun, pages = {19--28}, pmid = {24681328}, title = Template:Neither serotonin nor adenosine-dependent mechanisms preserve ventilatory capacity in ALS rats., url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4022482\&tool=pmcentrez\&rendertype=abstract}, volume = {197}, year = {2014} } </bibtex>
[4]<bibtex> @article{Dentel2013, abstract = {Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.}, author = {Dentel, Christel and Palamiuc, Lavinia and Henriques, Alexandre and Lannes, B\'{e}atrice and Spreux-Varoquaux, Odile and Gutknecht, Lise and Ren\'{e}, Fr\'{e}d\'{e}rique and Echaniz-Laguna, Andoni and {Gonzalez de Aguilar}, Jose-Luis and Lesch, Klaus Peter and Meininger, Vincent and Loeffler, Jean-Philippe and Dupuis, Luc}, doi = {10.1093/brain/aws274}, issn = {1460-2156}, journal = {Brain : a journal of neurology}, keywords = {Adult,Aged, 80 and over,Amyotrophic Lateral Sclerosis,Amyotrophic Lateral Sclerosis: epidemiology,Amyotrophic Lateral Sclerosis: pathology,Animals,Female,Humans,Male,Mice,Mice, Transgenic,Middle Aged,Muscle Spasticity,Muscle Spasticity: epidemiology,Muscle Spasticity: pathology,Nerve Degeneration,Nerve Degeneration: epidemiology,Nerve Degeneration: pathology,Serotonergic Neurons,Serotonergic Neurons: pathology}, month = mar, number = {Pt 2}, pages = {483--93}, pmid = {23114367}, title = Template:Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity., url = {http://www.ncbi.nlm.nih.gov/pubmed/23114367}, volume = {136}, year = {2013} } </bibtex>
