Histaminergic transmission slows progression of amyotrophic lateral sclerosis

Abstract

Background Histamine is an immune modulator, neuroprotective, and remyelinating agent, beneficially acting on skeletal muscles and promoting anti‐inflammatory features in amyotrophic lateral sclerosis (ALS) microglia. Drugs potentiating the endogenous release of histamine are in trial for neurological diseases, with a role not systematically investigated in ALS. Here, we examine histamine pathway associations in ALS patients and the efficacy of a histamine‐mediated therapeutic strategy in ALS mice. Methods We adopted an integrative multi‐omics approach combining gene expression profiles, copy number variants, and single nucleotide polymorphisms of ALS patients. We treated superoxide dismutase 1 (SOD1)‐G93A mice that recapitulate key ALS features, with the brain‐permeable histamine precursor histidine in the symptomatic phase of the disease and analysed the rescue from disease pathological signs. We examined the action of histamine in cultured SOD1‐G93A motor neuron‐like cells. Results We identified 13 histamine‐related genes deregulated in the spinal cord of two ALS patient subgroups, among which genes involved in histamine metabolism, receptors, transport, and secretion. Some histamine‐related genes overlapped with genomic regions disrupted by DNA copy number and with ALS‐linked pathogenic variants. Histidine treatment in SOD1‐G93A mice proved broad efficacy in ameliorating ALS features, among which most importantly lifespan, motor performance, microgliosis, muscle atrophy, and motor neurons survival in vivo and in vitro . Conclusions Our gene set/pathway enrichment analyses and preclinical studies started at the onset of symptoms establish that histamine‐related genes are modifiers in ALS, supporting their role as candidate biomarkers and therapeutic targets. We disclose a novel important role for histamine in the characterization of the multi‐gene network responsible for ALS and, furthermore, in the drug development process.

Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS

“…In SOD1-G93A mice, synaptic defects and dendritic spine loss start to be detected in cortical neurons concurrently with the onset of motor alterations [27,28], and then worsen in association with the full symptomatology. Previous results showing that histamine elicits neuroprotective actions on SOD1-G93A motor neurons [16], together with the present observation that histamine activates Hsps mechanisms, prompted us to examine whether histaminergic signaling could contrast dendritic spine loss in type I cortical motor neurons. Statistical comparisons of spine density in the apical and basal dendrite compartment of Golgi-stained M1 pyramidal neurons (Figure 4C) from WT, SOD1-G93A, and SOD1-G93A histidine-injected mice reveals significant group differences (Figure 4D,E; basal dendrites: F(2, 70) = 37,045, p < 0.05); apical dendrites: F(2, 71) = 53,876, p < 0.01).…”

“…Hsps are important regulators of inflammatory conditions, by acting in microglia and astrocytes to inhibit nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and to prevent the over-production of inflammatory mediators such as nitric oxide (NO) synthase and cycloxygenase-2 [6]. We have previously demonstrated that histamine is able to polarize the SOD1-G93A microglia towards an anti-inflammatory phenotype both in vitro and in vivo, by decreasing NF-κB and detrimental M1-like markers, while increasing beneficial M2-like markers [16,17]. Here, we have analyzed the effects of histamine on Hsps proteins.…”

“…We have previously shown that histamine elicits neuroprotective actions on SOD1-G93A motor neurons, particularly by restoring a proper mitochondrial metabolism and activating the AKT/ERK1/2 pro-survival pathway [16]. As an increased content of Hsps is a well-known neuroprotective mechanism in ALS [6], we investigated whether histamine directly affects Hsps proteins also in motor neuron-like cells expressing the SOD1-G93A mutation.…”

“…Previous studies have shown that animal models of ALS lack the stress-induced up-regulation of Hsps [7] and that a late stage treatment with drugs activating the HSR delays disease progression and prevents protein aggregation in the SOD1 mouse model of ALS [24]. We have previously demonstrated that the CNS permeable histamine precursor histidine increases motor neuron survival and decreases neuroinflammation in the spinal cord, when administered to SOD1-G93A mice from the onset of the disease symptoms until end stage [16]. In order to investigate whether the beneficial histaminergic signaling also proceeds in vivo through the Hsps axis, we evaluated the levels of Hsp70 and GRP78 in the spinal cords of SOD1-G93A mice after the treatment with 100 mg/kg histidine.…”

“…Our previous studies have shown that histamine-related genes are dysregulated in the spinal cord and cortex of both sporadic ALS patients and SOD1-G93A mice during different phases of disease progression. Furthermore, a pharmacological approach increasing the CNS histamine content in SOD1-G93A mice ameliorates various pathological features of ALS, most importantly life span, motor performance, neuroinflammation, muscle atrophy and motor neuron death [16]. Finally, histamine induces an anti-inflammatory profile in SOD1-G93A microglia, and sustains the survival of SOD1-G93A motor neurons in culture [16,17].…”