Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model

Yisarakun, Waranurin; Supornsilpchai, Weera; Chantong, Chattraporn; Srikiatkhachorn, Anan; Grand, Supang Maneesri-le

doi:10.1016/j.mvr.2014.04.012

Cited by 18 publications

(20 citation statements)

References 35 publications

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“…The liver morphology was normal, as well as the levels of three main liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) as previously described (Yisarakun et al, 2014).…”

Section: Resultsmentioning

confidence: 93%

“…In our previous studies, the trigeminovascular nociceptive system responded differently between acute and chronic treatment with APAP in both neural and vascular compartments. While short-term treatment with APAP (200 mg/kg body weight) could attenuate the CSDinduced alteration in the trigeminal nociception (Supornsilpchai et al, 2010a(Supornsilpchai et al, , 2010b and cerebral microvessels (Yisarakun et al, 2014), the opposite responses were observed in the rat with chronic treatment. The greater degree of the alteration in both cortical neurons (Supornsilpchai et al, 2010a(Supornsilpchai et al, , 2010b and cerebral microvessels (Yisarakun et al, 2014) induced by CSD were observed in those with chronic APAP treatment (Supornsilpchai et al, 2010a(Supornsilpchai et al, , 2010bYisarakun et al, 2014).…”

Section: Introductionmentioning

confidence: 94%

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Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model

et al. 2015

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 94%

Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model

et al. 2015

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“…Each ampoule contained 300 mg/2 mL. The dose of acetaminophen used in the present experiments was 200 mg/kg [6–8, 11]. Normal saline was administered to rats in the vehicle control group.…”

Section: Methodsmentioning

confidence: 99%

“…The volume of all drug injections was calculated according to standard criteria (intraperitoneally 10 mL/kg) [12]. Doses of analgesics were chosen based on the presence of efficacy without serious adverse effects [6–8, 10, 11]. Intraperitoneal injections of the calculated dose or vehicle control were made daily from 8:00 to 9:00 am .…”

Section: Methodsmentioning

confidence: 99%

Neural hyperactivity in the amygdala induced by chronic treatment of rats with analgesics may elucidate the mechanisms underlying psychiatric comorbidities associated with medication-overuse headache

2017

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BackgroundPatients with medication-overuse headache suffer not only from chronic headache, but often from psychiatric comorbidities, such as anxiety and depression. The mechanisms underlying these comorbidities are unclear, but the amygdala is likely to be involved in their pathogenesis. To investigate the mechanisms underlying the comorbidities we used elevated plus maze and open field tests to assess anxiety-like behavior in rats chronically treated with analgesics. We measured the electrical properties of neurons in the amygdala, and examined the cortical spreading depression (CSD)-evoked expression of Fos in the trigeminal nucleus caudalis (TNC) and amygdala of rats chronically treated with analgesics. CSD, an analog of aura, evokes Fos expression in the TNC of rodents suggesting trigeminal nociception, considered to be a model of migraine.ResultsIncreased anxiety-like behavior was seen both in elevated plus maze and open field tests in a model of medication overuse produced in male rats by chronic treatment with aspirin or acetaminophen. The time spent in the open arms of the maze by aspirin- or acetaminophen-treated rats (53 ± 36.1 and 37 ± 29.5 s, respectively) was significantly shorter than that spent by saline-treated vehicle control rats (138 ± 22.6 s, P < 0.001). Chronic treatment with the analgesics increased the excitability of neurons in the central nucleus of the amygdala as indicated by their more negative threshold for action potential generation (–54.6 ± 5.01 mV for aspirin-treated, –55.2 ± 0.97 mV for acetaminophen-treated, and –31.50 ± 5.34 mV for saline-treated rats, P < 0.001). Chronic treatment with analgesics increased the CSD-evoked expression of Fos in the TNC and amygdala [18 ± 10.2 Fos-immunoreactive (IR) neurons per slide in the amygdala of rats treated with aspirin, 11 ± 5.4 IR neurons per slide in rats treated with acetaminophen, and 4 ± 3.7 IR neurons per slide in saline-treated control rats, P < 0.001].ConclusionsChronic treatment with analgesics can increase the excitability of neurons in the amygdala, which could underlie the anxiety seen in patients with medication-overuse headache.Electronic supplementary materialThe online version of this article (doi:10.1186/s12868-016-0326-z) contains supplementary material, which is available to authorized users.

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“…Although this did not achieve statistical significance., it does suggest that the paracetamol diet may have caused some low-level damage in some mice which is not measurable in the circulation, at least not after 6 weeks of treatment. Previous animal studies that have dosed once daily, via intraperitoneal injection or oral gavage, for 30-99 days with 75-300mg/kg showed no evidence of toxicity as assessed by liver function tests (7–9). Our study, which modeled a more clinically relevant exposure to paracetamol at regular intervals over a full day, as it was consumed in the diet, rather than once daily, appears to confirm these findings.…”

Section: Discussionmentioning

confidence: 87%

N‐Acetyl cysteine does not prevent liver toxicity from chronic low‐dose plus subacute high‐dose paracetamol exposure in young or old mice

Kane

Huizer-Pajkos

Mach

et al. 2016

Fundamemntal Clinical Pharma

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Paracetamol is an analgesic commonly used by people of all ages, which is well documented to cause severe hepatotoxicity with acute over-exposures. The risk of hepatotoxicity from non-acute paracetamol exposures is less extensively studied, and this is the exposure most common in older adults. Evidence on the effectiveness of N-acetyl cysteine (NAC) for non-acute paracetamol exposures, in any age group, is lacking. This study aimed to examine the effect of long-term exposure to therapeutic doses of paracetamol and sub-acute paracetamol over-exposure, in young and old mice, and to investigate whether NAC was effective at preventing paracetamol hepatotoxicity induced by these exposures. Young and old male C57BL/6 mice were fed a paracetamol-containing (1.33g/kg food) or control diet for 6 weeks. Mice were then dosed orally 8 times over 3 days with additional paracetamol (250mg/kg) or saline, followed by either one or two doses of oral NAC (1200mg/kg) or saline. Chronic low-dose paracetamol exposure did not cause hepatotoxicity in young or old mice, measured by serum alanine aminotransferase (ALT) elevation, and confirmed by histology and a DNA fragmentation assay. Sub-acute paracetamol exposure caused significant hepatotoxicity in young and old mice, measured by biochemistry (ALT) and histology. Neither a single nor double dose of NAC protected against this toxicity from sub-acute paracetamol in young or old mice. This finding has important clinical implications for treating toxicity due to different paracetamol exposure types in patients of all ages, and implies a need to develop new treatments for sub-acute paracetamol toxicity.

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Chronic paracetamol treatment increases alterations in cerebral vessels in cortical spreading depression model

Cited by 18 publications

References 35 publications

Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model

Up-regulation of calcitonin gene-related peptide in trigeminal ganglion following chronic exposure to paracetamol in a CSD migraine animal model

Neural hyperactivity in the amygdala induced by chronic treatment of rats with analgesics may elucidate the mechanisms underlying psychiatric comorbidities associated with medication-overuse headache

N‐Acetyl cysteine does not prevent liver toxicity from chronic low‐dose plus subacute high‐dose paracetamol exposure in young or old mice

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