The Neuroprotection Exerted by Memantine, Minocycline and Lithium, against Neurotoxicity of CSF from Patients with Amyotrophic Lateral Sclerosis, Is Antagonized by Riluzole

Abstract

In a recent study we found that cerebrospinal fluids (CSFs) from amyotrophic lateral sclerosis (ALS) patients caused 20-30% loss of cell viability in primary cultures of rat embryo motor cortex neurons. We also found that the antioxidant resveratrol protected against such damaging effects and that, surprisingly, riluzole antagonized its protecting effects. Here we have extended this study to the interactions of riluzole with 3 other recognized neuroprotective agents, namely memantine, minocycline and lithium. We found: (1) by itself riluzole exerted neurotoxic effects at concentrations of 3-30 µ<smlcap>M</smlcap>; this cell damage was similar to that elicited by 30 µ<smlcap>M</smlcap> glutamate and a 10% dilution of ALS/CSF; (2) memantine (0.1-30 µ<smlcap>M</smlcap>), minocycline (0.03-1 µ<smlcap>M</smlcap>) and lithium (1-80 µg/ml) afforded 10-30% protection against ALS/CSF-elicited neurotoxicity, and (3) at 1-10 µ<smlcap>M</smlcap>, riluzole antagonized the protection afforded by the 3 agents. These results strongly support the view that at the riluzole concentrations reached in the brain of patients, the neurotoxic effects of this drug could be masking the potential neuroprotective actions of new compounds being tested in clinical trials. Therefore, in the light of the present results, the inclusion of a group of patients free of riluzole treatment may be mandatory in future clinical trials performed in ALS patients with novel neuroprotective compounds.

Downregulation of Homer1b/c in SOD1 G93A Models of ALS: A Novel Mechanism of Neuroprotective Effect of Lithium and Valproic Acid

“…The effects of lithium on ALS are mainly dependent on the beneficial therapeutic window for lithium treatment, the blood lithium levels, and route of administration and frequency [29]. It has recently been shown that neuroprotection by lithium is antagonized by riluzole (the only FDA-approved drug for ALS), suggesting that the drug’s neurotoxic effects may cover up the potential neuroprotective action of lithium [30]. The beneficial effect of VPA has been documented in different neurodegenerative experimental models, including ALS [31].…”

Cerebrospinal fluid cytotoxicity does not affect survival in amyotrophic lateral sclerosis

“…[8][9][10] Median survival time among European patients with ALS is 30 months from the onset of symptoms and 19 months from time of diagnosis. [8][9][10] Median survival time among European patients with ALS is 30 months from the onset of symptoms and 19 months from time of diagnosis.…”

“…[8][9][10] Median survival time among European patients with ALS is 30 months from the onset of symptoms and 19 months from time of diagnosis. We aimed to study the potential clinical consequences associated with the cytotoxicity of CSF in a cohort of patients with ALS.…”

Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of&nbsp;cerebral ischemia rats and improves behavioral&nbsp;deficits

“…Minocycline, a semisynthetic tetracycline antibiotic that effectively crosses the blood–brain barrier, has been reported to have significant neuroprotective effects in cognitive impairment,24,25 schizophrenia,26 cerebral ischemia,27 amyotrophic lateral sclerosis,28 Alzheimer’s disease,25,29 Huntington’s disease,30,31 and Parkinson’s diseases 32. Minocycline can inhibit ischemic-induced inflammation,33,34 astrocyte reactivation,35 microglia activation,32 oxidative stress,36,37 apoptosis,37,38 and so on.…”