Hindbrain raphe stimulation boosts cyclic adenosine monophosphate and signaling proteins in the injured spinal cord

Carballosa-Gonzalez, Melissa M.; Vitores, Alberto; Hentall, Ian D.

doi:10.1016/j.brainres.2013.11.013

Cited by 8 publications

(17 citation statements)

References 58 publications

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“…Microstimulation in the NRM has been clearly demonstrated to release serotonin in the rat’s spinal cord (Hentall et al, 2006). NRM stimulation with parameters used in this study (30 μA pulses in 8 Hz trains) has also been found to increase trophic signaling molecules cyclic AMP, pPKA and pCREB in the injured thoracic spinal cord of the rat that are blocked by the 5-HT7 receptor antagonist pimozide (Carballosa-Gonzalez et al, 2014). Furthermore, some findings with re-uptake inhibitors suggest that serotonin dampens the symptoms of EAE (White et al, 1992; Vollmar et al, 2009).…”

Section: Discussionmentioning

confidence: 79%

Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

et al. 2017

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Multiple sclerosis (MS), a neuroinflammatory disease, has few treatment options, none entirely adequate. We studied whether prolonged electrical stimulation of a hindbrain region (the nucleus raphe magnus) can attenuate experimental autoimmune encephalomyelitis, a murine model of MS induced by MOG35-55 injection. Eight days after symptoms emerged, a wireless electrical stimulator with a connectorless protruding microelectrode was implanted cranially, and daily intermittent stimulation of awake, unrestrained mice began immediately. The thoracic spinal cord was analyzed for changes in histology (on day 29) and gene expression (on day 37), with a focus on myelination and cytokine production. Controls, with inactive implants, showed a phase of disease exacerbation on days 19–25 that stimulation for >16 days eliminated. Prolonged stimulation also reduced infiltrating immune cells and increased numbers of myelinated axons. It additionally lowered gene expression for some pro-inflammatory cytokines (interferon gamma and tumor necrosis factor) and for platelet-derived growth factor receptor alpha, a marker of oligodendrocyte precursors, while raising it for myelin basic protein. Restorative treatments for MS might profitably consider ways to stimulate the raphe magnus, directly or via its inputs, or to emulate its serotonergic and peptidergic output.

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Section: Discussionmentioning

confidence: 79%

Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

et al. 2017

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“…This test requires motor and coordination abilities, which involve different areas in the brain and spinal cord. The rapid drop of rotarod performance may reflect the rapid penetration and action of the drug in the central nervous system, as reported before [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 55%

“…The drug was delivered every 2 days, to reduce stress in mice due to manipulations, at the double of the concentration (1 mg/kg). There are reports showing that the drug is effective in the brain and spinal cord at 1 h after intraperitoneal injection of 1 mg/kg of pimozide with behavioral effects lasting up to 24 h [ 16 , 17 ] with half-life of 55 h in the brain [ 8 ]. Moreover, subcutaneous injection of 0.63 mg/kg pimozide resulted in 30 pg of pimozide per mg of brain tissues after 8 h and 6 pg after 32 h [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis

Pozzi¹,

Thammisetty²,

Julien

2018

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survival in SOD1G93A mice. In TDP-43A315T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1G93A mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.Electronic supplementary materialThe online version of this article (10.1007/s13311-018-0634-3) contains supplementary material, which is available to authorized users.

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“…It was shown that stimulation of the NRM acutely increases levels of spinal cord PKA, cAMP and CREB, signaling molecules with important roles in development, repair and long-term potentiation. Interestingly, these beneficial effects were elicited at quite low stimulation frequencies (4–8 Hz), not the high frequencies (typically 50–150 Hz) used for nearly all other indications of DBS (Hentall et al, 2006; Carballosa-Gonzalez et al, 2014). This is relevant because while high-frequency DBS is thought to functionally inhibit its target, low-frequency stimulation is considered stimulatory and, in the present case, should lead to activation of PAG and NRM and the release of modulatory neurotransmitters in the spinal cord (Hentall and Gonzalez, 2012).…”

Section: Discussionmentioning

confidence: 99%

Deep Brain Stimulation Improves the Symptoms and Sensory Signs of Persistent Central Neuropathic Pain from Spinal Cord Injury: A Case Report

Jermakowicz

Hentall

Jagid

et al. 2017

Front. Hum. Neurosci.

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Central neuropathic pain (CNP) is a significant problem after spinal cord injury (SCI). Pharmacological and non-pharmacological approaches may reduce the severity, but relief is rarely substantial. While deep brain stimulation (DBS) has been used to treat various chronic pain types, the technique has rarely been used to attenuate CNP after SCI. Here we present the case of a 54-year-old female with incomplete paraplegia who had severe CNP in the lower limbs and buttock areas since her injury 30 years prior. She was treated with bilateral DBS of the midbrain periaqueductal gray (PAG). The effects of this stimulation on CNP characteristics, severity and pain-related sensory function were evaluated using the International SCI Pain Basic Data Set (ISCIPBDS), Neuropathic Pain Symptom Inventory (NPSI), Multidimensional Pain Inventory and Quantitative Sensory Testing before and periodically after initiation of DBS. After starting DBS treatment, weekly CNP severity ratings rapidly decreased from severe to minimal, paralleled by a substantial reduction in size of the painful area, reduced pain impact and reversal of pain-related neurological abnormalities, i.e., dynamic-mechanical and cold allodynia. She discontinued pain medication on study week 24. The improvement has been consistent. The present study expands on previous findings by providing in-depth assessments of symptoms and signs associated with CNP. The results of this study suggest that activation of endogenous pain inhibitory systems linked to the PAG can eliminate CNP in some people with SCI. More research is needed to better-select appropriate candidates for this type of therapy. We discuss the implications of these findings for understanding the brainstem’s control of chronic pain and for future progress in using analgesic DBS in the central gray.

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Hindbrain raphe stimulation boosts cyclic adenosine monophosphate and signaling proteins in the injured spinal cord

Cited by 8 publications

References 58 publications

Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

Prolonged stimulation of a brainstem raphe region attenuates experimental autoimmune encephalomyelitis

Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis

Deep Brain Stimulation Improves the Symptoms and Sensory Signs of Persistent Central Neuropathic Pain from Spinal Cord Injury: A Case Report

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