Acute desipramine restores presynaptic cortical defects in murine experimental autoimmune encephalomyelitis by suppressing central CCL5 overproduction

Abstract

BACKGROUND AND PURPOSEAltered glutamate exocytosis and cAMP production in cortical terminals of experimental autoimmune encephalomyelitis (EAE) mice occur at the early stage of disease (13 days post-immunization, d.p.i.). Neuronal defects were paralleled by overexpression of the central chemokine CCL5 (also known as RANTES), suggesting it has a role in presynaptic impairments. We propose that drugs able to restore CCL5 content to physiological levels could also restore presynaptic defects. Because of its efficacy in controlling CCL5 overexpression, desipramine (DMI) appeared to be a suitable candidate to test our hypothesis. EXPERIMENTAL APPROACHControl and EAE mice at 13 d.p.i. were acutely or chronically administered DMI and monitored for behaviour and clinical scores. Noradrenaline and glutamate release, cAMP, CCL5 and TNF-α production were quantified in cortical synaptosomes and homogenates. Peripheral cytokine production was also determined. KEY RESULTSNoradrenaline exocytosis and α2-adrenoeceptor-mediated activity were unmodified in EAE mice at 13 d.p.i. when compared with control. Acute, but not chronic, DMI reduced CCL5 levels in cortical homogenates of EAE mice at 13 d.p.i., but did not affect peripheral IL-17 and TNF-α contents or CCL5 plasma levels. Acute DMI caused a long-lasting restoration of glutamate exocytosis, restored endogenous cAMP production and impeded the shift from inhibition to facilitation of the CCL5-mediated control of glutamate exocytosis. Finally, DMI ameliorated anxiety-related behaviour but not motor activity or severity of clinical signs. CONCLUSIONSWe propose DMI as an add-on therapy to normalize neuropsychiatric symptoms in multiple sclerosis patients at the early stage of the disease.

Behavioral assessment of neuropathic pain, fatigue, and anxiety in experimental autoimmune encephalomyelitis (EAE) and attenuation by interleukin-10 gene therapy

“…These symptoms are rarely assessed in rodent models, despite their frequent association with MS. Assessment of nociceptive hypersensitivity in relapsing remitting models is limited, but several studies have demonstrated pharmacological reversal of allodynia (Khan et al, 2014; Lu et al, 2012; Lynch et al, 2008; Ramos et al, 2010; Schmitz et al, 2014; Sloane et al, 2009; Thibault et al, 2011; Tian et al, 2013). While anxiety behaviors are a known feature in EAE models (Acharjee et al, 2013; Peruga et al, 2011; Pollak et al, 2000), only two studies have evaluated therapeutic modulation (Di Prisco et al, 2014; Haji et al, 2012). Our study is the first to quantify such a breadth of EAE-associated behaviors, and further introduces a measure of fatigue, as well as demonstrating reversal with XT-101-R.…”

Functional adaptation of presynaptic chemokine receptors in EAE mouse central nervous system

“…This possibility is intriguing when considering that, in EAE mice at the early stage of disease, cyclic adenosine monophosphate production was drastically reduced in cortical nerve endings and forskolin could no more release glutamate (Di Prisco et al, ), suggesting that in these mice CCR oligomers do not couple efficiently to adenylyl cyclase (AC). Interestingly, the loss of function of AC was strictly related to CCL5 overexpression, since pharmacological interventions restoring CCL5 amount to physiological level also recovered AC activity and its negative coupling to CCR oligomers (Di Prisco et al, ). These observations led us to propose that the loss of function of AC in cortical glutamatergic nerve terminals might have favored the unusual coupling of CCRs to a dissimilar enzymatic pathway, giving the rationale for the switch from inhibition to facilitation of the presynaptic CCL5‐mediated control of glutamate exocytosis.…”

“…Female mice (C57BL/6; 18–20 g, 6–8 weeks) were immunized with myelin oligodendrocyte glycoprotein (MOG) 35–55 according to a standard protocol previously described (Di Prisco et al, ). Briefly, animals were subcutaneously injected with incomplete Freund's adjuvant containing 4 mg/ml Mycobacterium tuberculosis (strain H37Ra) and 200 µg of the MOG 35–55 peptide.…”

“…Interestingly, recent studies provide convincing evidence that (i) CCL5 can modulate glutamate outflow at glutamatergic nerve endings in healthy conditions (Di Prisco et al, ; Musante et al, ), (ii) glutamate exocytosis as well as its CCL5‐mediated presynaptic control are altered in EAE mice (Di Prisco et al, ), and (iii) drugs restoring CCL5 overproduction to physiological level also recovered presynaptic glutamate defects (Di Prisco et al, ).…”

“…Glutamate is the major excitatory neurotransmitter in CNS, where it mediates important physiological functions (i.e., synaptic plasticity, learning, and memory) but also excitotoxic degenerative processes. Increased glutamate levels because of altered release efficiency have been observed in the cerebrospinal fluid of MS patients (Sarchielli et al, ) and in EAE mice (Di Prisco et al, ) that might influence both chemical transmission and inflammatoty processes (Fallarino et al, ; Ganor et al, ; Sarchielli et al, ).…”