The neuropathy-protective agent acetyl-l-carnitine activates protein kinase C-γ and MAPKs in a rat model of neuropathic pain

Mannelli, Lorenzo Di Cesare; Ghelardini, Carla; Toscano, Anna; Pacini, Alessandra; Bartolini, Alessandro

doi:10.1016/j.neuroscience.2009.11.021

Cited by 35 publications

(91 citation statements)

References 44 publications

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“…First, this protein kinase is able to directly activate ERK1/2 members of the mitogen-activated protein kinases family, p38 and SAP/c-jun terminal kinase, which are involved in pain sensitization and several injury-activated pathways [53-55]. Second, spinal activation of PKCγ involves translocation from the cytosol to binding domains at cell membranes of dorsal horn neurons, increases release of glutamate in the spinal cord, and sensitizes the spinothalamic tract and other dorsal horn neurons, and formalin-induced release of glutamate is prevented by blockade of PKCγ [30,55-57].…”

Section: Discussionmentioning

confidence: 99%

PKCγ Receptor Mediates Visceral Nociception and Hyperalgesia following Exposure to PTSD-Like Stress in the Spinal Cord of Rats

Chen

et al. 2013

Mol Pain

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BackgroundClinical studies indicate that patients with post-traumatic stress disorder (PTSD) frequently share comorbidity with numerous chronic pain conditions. However, the sustained effects of PTSD-like stress over time on visceral nociception and hyperalgesia have been rarely studied, and the underlying mechanisms of stress-induced modulation of visceral hyperalgesia remain elusive. The purpose of this study was to investigate the characterization of visceral nociception and hyperalgesia over time in rats exposed to PTSD-like stress, and to explore the potential role of protein kinase C gamma (PKCγ) in mediating visceral hyperalgesia following exposure to PTSD-like stress.ResultsOn day 1, the rats exposed to single-prolonged stress (SPS, an established animal model for PTSD) exhibited an analgesic response and its visceromotor response (VMR) to graded colorectal distention (CRD) at 40 and 60 mmHg was reduced compared with the control group (all P < 0.05). On day 6, the VMR returned to the baseline value. However, as early as 7 days after SPS, VMR dramatically increased compared with its baseline value and that in the controls (all P < 0.001) and this increase persisted for 28 days, with the peak on day 9. Abdominal withdrawal reflex (AWR) scores were higher in SPS rats than in controls on days 7, 9, 14, 21 and 28 (all P < 0.001). Intrathecal administration of GF109203X (an inhibitor of PKC gamma), attenuated the SPS-induced increase in both VMR and AWR scores on days 7, 14, 21 and 28 (all P < 0.05). PKCγ protein expression determined by immunofluorescence was reduced in the spinal cord within 3 days after the exposure to SPS (P < 0.01), which returned to normal levels between days 4 and 6, and significantly increased from day 7, and this increase was maintained on days 14, 21, and 28 (all P < 0.001), with the peak on day 9. In addition, Western blotting showed a consistent trend in the changes of PKCγ protein expression.ConclusionsThe modified SPS alters visceral sensitivity to CRD, and contributes to the maintenance of visceral hyperalgesia, which is associated with enhanced PKCγ expression in the spinal cord. Functional blockade of the PKCγ receptors attenuates SPS-induced visceral hyperalgesia. Thus, the present study identifies a specific molecular mechanism for visceral hyperalgesia which may pave the way for novel therapeutic strategies for PTSD-like conditions.

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Section: Discussionmentioning

confidence: 99%

PKCγ Receptor Mediates Visceral Nociception and Hyperalgesia following Exposure to PTSD-Like Stress in the Spinal Cord of Rats

Chen

et al. 2013

Mol Pain

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“…ALC facilitates the uptake of acetyl-CoA into the mitochondria during fatty acid oxidation, enhances acetylcholine production, and stimulates protein and membrane phospholipids' synthesis, provides a substrate reservoir for cellular energy production, thereby preventing excessive neuronal cell death [15][16][17].…”

Section: Acetylcarnitinementioning

confidence: 99%

“…ALC administration demonstrates the effectiveness to alleviating pain associated with methadone withdrawal syndrome and sciatica from herniated discs [15,63,64].…”

Section: Other Effectsmentioning

confidence: 99%

Carnitine derivatives

Malaguarnera

2012

Current Opinion in Gastroenterology

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“…In general, drugs available counter hyperalgesic symptomatology of neuropathy, but do not affect the course of these diseases. Neuroprotective and/or neurorestorative effects elicited by pharmacological treatments were reported only rarely [1]. …”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Activity of Thioctic Acid in Central Nervous System Lesions Consequent to Peripheral Nerve Injury

Tomassoni

Amenta

Mannelli

et al. 2013

BioMed Research International

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Peripheral neuropathies are heterogeneous disorders presenting often with hyperalgesia and allodynia. This study has assessed if chronic constriction injury (CCI) of sciatic nerve is accompanied by increased oxidative stress and central nervous system (CNS) changes and if these changes are sensitive to treatment with thioctic acid. Thioctic acid is a naturally occurring antioxidant existing in two optical isomers (+)- and (−)-thioctic acid and in the racemic form. It has been proposed for treating disorders associated with increased oxidative stress. Sciatic nerve CCI was made in spontaneously hypertensive rats (SHRs) and in normotensive reference cohorts. Rats were untreated or treated intraperitoneally for 14 days with (+/−)-, (+)-, or (−)-thioctic acid. Oxidative stress, astrogliosis, myelin sheets status, and neuronal injury in motor and sensory cerebrocortical areas were assessed. Increase of oxidative stress markers, astrogliosis, and neuronal damage accompanied by a decreased expression of neurofilament were observed in SHR. This phenomenon was more pronounced after CCI. Thioctic acid countered astrogliosis and neuronal damage, (+)-thioctic acid being more active than (+/−)- or (−)-enantiomers. These findings suggest a neuroprotective activity of thioctic acid on CNS lesions consequent to CCI and that the compound may represent a therapeutic option for entrapment neuropathies.

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The neuropathy-protective agent acetyl-l-carnitine activates protein kinase C-γ and MAPKs in a rat model of neuropathic pain

Cited by 35 publications

References 44 publications

PKCγ Receptor Mediates Visceral Nociception and Hyperalgesia following Exposure to PTSD-Like Stress in the Spinal Cord of Rats

PKCγ Receptor Mediates Visceral Nociception and Hyperalgesia following Exposure to PTSD-Like Stress in the Spinal Cord of Rats

Carnitine derivatives

Neuroprotective Activity of Thioctic Acid in Central Nervous System Lesions Consequent to Peripheral Nerve Injury

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