Changes in the endocannabinoid signaling system in CNS structures of TDP-43 transgenic mice: relevance for a neuroprotective therapy in TDP-43-related disorders

Abstract

Because of their neuroprotective properties, cannabinoids are being investigated in neurodegenerative disorders, mainly in preclinical studies. These disorders also include amyotrophic lateral sclerosis (ALS), a degenerative disease produced by the damage of the upper and lower motor neurons leading to muscle denervation, atrophy and paralysis. The studies with cannabinoids in ALS have been conducted exclusively in a transgenic mouse model bearing mutated forms of human superoxide dismutase-1, the first gene that was identified in relation with ALS. The present study represents the first attempt to investigate the endocannabinoid system in an alternative model, the transgenic mouse model of TAR-DNA binding protein-43 (TDP-43), a protein related to ALS and also to frontotemporal dementia. We used these mice for behavioral and histological characterization at an early symptomatic phase (70-80 days of age) and at a post-symptomatic stage (100-110 days of age). TDP-43 transgenic mice exhibited a worsened rotarod performance at both disease stages. This was accompanied by a loss of motor neurons in the spinal cord (measured by Nissl staining) and by reactive microgliosis (measured by Iba-1 immunostaining) at the post-symptomatic stage. We also detected elevated levels of the CB2 receptor (measured by qRT-PCR and western blotting) in the spinal cord of these animals. Double-staining studies confirmed that this up-regulation occurs in microglial cells in the post-symptomatic stage. Some trends towards an increase were noted also for the levels of endocannabinoids, which in part correlate with a small reduction of FAAH. Some of these parameters were also analyzed in the cerebral cortex of TDP-43 transgenic mice, but we did not observe any significant change, in agreement with the absence of anomalies in cognitive tests. In conclusion, our data support the idea that the endocannabinoid signaling system, in particular the CB2 receptor, may serve for the development of a neuroprotective therapy in TDP-43-related disorders. We are presently engaged in pharmacological experiments to investigate this possibility.

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…However, to determine the changes in CB 1 R remains controversial, with a study reporting downregulatory responses in the spinal cord of SOD-1 mutant mice, even at early presymptomatic phases [164], which may predispose motor neurons to excitotoxic events, given the role that CB 1 R play in the control of glutamate homeostasis. However, a further study conducted in the same mutant mice did not find any changes in CB 1 R in the spinal cord [161], and this has been recently confirmed in TDP-43 transgenic mice, too [162].…”

“…Thus, the levels of anandamide and 2-AG are elevated in the spinal cord of SOD-1 mutant mice [156,160], in parallel to an increase in the expression of N-acyl-phosphatidylethanolamine-selective phospholipase D, the enzyme that synthesizes anandamide, but no changes in diacylglycerol lipase, the enzyme that synthesizes 2-AG, and in FAAH and MAGL, the 2 major degradative enzymes for the 2 major endocannabinoids [161]. In addition, CB 2 R experience an important upregulatory response in the spinal cord of SOD-1 mutant and TDP-43 transgenic mice [158,161,162], as well as in patients with ALS [163]. This upregulation appears to occur predominantly in microglial elements recruited at lesioned sites [162,163], so that it may facilitate the beneficial effects derived from selectively targeting this receptor in the control of microglial toxicity for motor neurons.…”

“…In addition, CB 2 R experience an important upregulatory response in the spinal cord of SOD-1 mutant and TDP-43 transgenic mice [158,161,162], as well as in patients with ALS [163]. This upregulation appears to occur predominantly in microglial elements recruited at lesioned sites [162,163], so that it may facilitate the beneficial effects derived from selectively targeting this receptor in the control of microglial toxicity for motor neurons. However, to determine the changes in CB 1 R remains controversial, with a study reporting downregulatory responses in the spinal cord of SOD-1 mutant mice, even at early presymptomatic phases [164], which may predispose motor neurons to excitotoxic events, given the role that CB 1 R play in the control of glutamate homeostasis.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…In addition, elevated levels of CB2 are detected in the spinal cord both of SOD-1 mutants (591) and TDP-43 transgenic mice, another model of ALS (245), and, importantly, also in patients with the disease (932). No changes in CB1 expression in the spinal cord are instead found (245,591).…”

Altered striatal endocannabinoid signaling in a transgenic mouse model of spinocerebellar ataxia type-3

“…In general, both dysregulation and endogenous protection are active in numerous neurodegenerative pathologies, both acute (e.g., stroke [6], brain trauma [7], spinal injury [8]) and chronic progressive disorders (e.g., Alzheimer’s disease [9], Parkinson’s disease [10], Huntington’s chorea [11,12], amyotrophic lateral sclerosis [13,14] and others [2]). Such responses have also been seen in autosomal-dominant spinocerebellar ataxias (SCAs; [15–17]), a group of inherited neurodegenerative disorders that mainly affect the cerebellum and its afferent/efferent structures, in which motor discoordination (“ataxia”) is the key symptom [18–21].…”