Pharmacokinetics of vanillin and its effects on mechanical hypersensitivity in a rat model of neuropathic pain

Beaudry, Francis; Ross, Andréanne; Lema, Pablo; Vachon, Pascal

doi:10.1002/ptr.2975

Cited by 68 publications

(54 citation statements)

References 38 publications

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“…Compared to our previous results where the reaction time on the Hargreaves decreased to 5 sec in neuropathic animal with the sciatic nerve ligation model, the animals with the caudoputamenthalamus lesions had a longer reaction time (7-9 sec) following the 2 µL collagenase solution injection which suggests that the pain is not as severe in these animals (Guenette et al, 2007;Beaudry et al, 2010). However with the 3 µL collagenase injection, pain threshold were similar to the animals with sciatic nerve injury.…”

Section: Discussioncontrasting

confidence: 63%

An Induced Hematoma in Caudoputamen Nuclei in Rats Causes Central Pain when the Thalamus is also Implicated and the Central Sensitization is Reversed with Gabapentin

Allam¹

2012

American Journal of Animal and Veterinary Sciences

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Problem statement:The objective of this study was to evaluate pain sensitisation in rats following the induction of an intracerebral hemorrhage by injecting a collagenase solution in the caudoputamen nucleus of the right basal ganglia and to evaluate gabapentin as an analgesic for central pain. Approach: Thirty male Sprague-Dawley rats weighing between 175-300 g were used. In a first experiment, 3 groups of 6 animals were used to evaluate pain threshold using the Hargreaves test (thermal sensitivity) only. Following 3 days of behavioral testing (baseline values), animals in each group were injected intracerebrally either with 0.5, 1 or 2 µL of a collagenase solution (0.5 U 2 µL −1 Type VII collagenase) inducing a hematoma in the right caudoputamen nucleus and/or thalamus. They were then tested for the next 9 consecutive days. In a second experiment, gabapentin was evaluated for the reversal of thermal hyperalgesia and mechanical allodynia (using von Frey filaments) following the intracerebral injection of 3 µL of the collagenase solution. Results: No pain-related behavioral changes were observed following injections with 0.5 and 1 µL of the collagenase solution. However with 2 µL, reaction times were significantly faster on days 3-7 in the right and left hind paws compared to baseline values. The lesion was localized only in the caudoputamen nucleus for animals receiving 0.5 and 1 µL of collagenase whereas lesions extended in the ipsilateral thalamic nuclei (lateral-dorsal and lateral-posterior nuclei) for animals receiving 2 µL of collagenase. Gabapentin reversed mechanical allodynia and thermal hyperalgesia in animals with caudoputamen and thalamic lesions. Conclusion: These preliminary results suggest that central pain was induced in rats with a collagenase-induced intracerebral hemorrhage localized in the thalamus and that mechanical allodynia and thermal hyperalgesia were reduced with gabapentin treatment.

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Section: Discussioncontrasting

confidence: 63%

An Induced Hematoma in Caudoputamen Nuclei in Rats Causes Central Pain when the Thalamus is also Implicated and the Central Sensitization is Reversed with Gabapentin

Allam¹

2012

American Journal of Animal and Veterinary Sciences

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“…Pharmacokinetics of vanillin. Studies in rats have shown that orally administered vanillin (100 mg/kg) is absorbed in the gastrointestinal tract and reaches a ;3 mM peak plasma concentration 4 hours after administration (Beaudry et al, 2010), suggesting poor uptake, rapid clearance, and/or excessive metabolism as has been described for curcumin (section III.A and Fig. 11).…”

Section: B Pharmacokinetics and Pharmacodynamics Of Curcumin Catabolmentioning

confidence: 90%

“…11). Intravenously administered vanillin is almost completely cleared or metabolized within 2 hours (Beaudry et al, 2010). Correspondingly, analysis of urine retrieved from rats 24 hours after an oral dose of vanillin (100 mg/kg) revealed that vanillin is extensively cleared via the renal system in conjugated form, mainly as vanillin glucuronide and sulfate (Kirwin and Galvin, 1993).…”

Section: B Pharmacokinetics and Pharmacodynamics Of Curcumin Catabolmentioning

confidence: 99%

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Golen²,

et al. 2013

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“…4). One of the limitations of using o-vanillin in vivo is its poor bioavailability, as has been reported previously for its isomer, vanillin (40). Due to this challenge, we administered a high dose twice to achieve an appreciable inhibitory effect in vivo.…”

Section: C29 Blocks Tlr2 Bacterial Agonist-induced Proinflammatory Genementioning

confidence: 98%

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

Mistry¹,

Laird²,

Schwarz³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

137

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Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C 16 H 15 NO 4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors.small molecule inhibitor | BB loop | TLR2 pocket | CADD T oll-like receptors (TLRs) are type I transmembrane receptors that detect conserved "pathogen-associated molecular patterns" from microbes, as well as host-derived "danger-associated molecular patterns" (1). TLR2 heterodimerizes with TLR6 or TLR1 to recognize diacyl lipopeptides or triacyl lipopeptides, respectively (2, 3), present in gram-positive and gram-negative bacteria (4-9).Ligand engagement of TLR2/1 or TLR2/6 activates the myeloid differentiation primary response gene 88 (MyD88)-dependent pathway (i.e., nuclear translocation of NF-κB, activation of MAPKs), resulting in production of proinflammatory cytokines (10). Dysregulated TLR2 signaling has been implicated in numerous diseases (e.g., sepsis, atherosclerosis, tumor metastasis, ischemia/reperfusion injury) (11)(12)(13)(14). Several inhibitors of TLR2 signaling have been developed (15-18), yet none is licensed for human use. A better understanding of the Toll/IL-1 receptor resistance (TIR) domain interactions involved in TLR2 signaling could lead to novel therapeutic agents.Both TLRs and adapter proteins contain a cytoplasmic TIR domain that mediates homotypic and heterotypic interactions ...

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Pharmacokinetics of vanillin and its effects on mechanical hypersensitivity in a rat model of neuropathic pain

Cited by 68 publications

References 38 publications

An Induced Hematoma in Caudoputamen Nuclei in Rats Causes Central Pain when the Thalamus is also Implicated and the Central Sensitization is Reversed with Gabapentin

An Induced Hematoma in Caudoputamen Nuclei in Rats Causes Central Pain when the Thalamus is also Implicated and the Central Sensitization is Reversed with Gabapentin

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

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