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Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice.

Lim HY, Albuquerque B, Häussler A, Myrczek T, Ding A, Tegeder I - J. Cell. Mol. Med. (2012)

Bottom Line: Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal.Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth.A deficiency in this mechanism may increase the risk for injury-associated chronic pain.

View Article: PubMed Central - PubMed

Affiliation: Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany.

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Progranulin-deficient (Grn−/−) mice showed stronger nociceptive sensitivity after nerve injury than wild-type mice. PGRN knockout (Grn−/−) mice and their wild-type control mice (n = 8 per group, four male, four female, 10–12 weeks at the time of surgery) were tested for their mechanical allodynia (A), cold allodynia (B), heat hyperalgesia (C) and motor functions (D) as in Figure 4. Data are means ± S.E.M. Comparison of the results with ANOVA revealed statistically significant differences between Grn−/− and wild-type mice for the percentage change of mechanical, cold and heat nociception and for the RotaRod running time as indicated with asterisks (P < 0.05).
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fig05: Progranulin-deficient (Grn−/−) mice showed stronger nociceptive sensitivity after nerve injury than wild-type mice. PGRN knockout (Grn−/−) mice and their wild-type control mice (n = 8 per group, four male, four female, 10–12 weeks at the time of surgery) were tested for their mechanical allodynia (A), cold allodynia (B), heat hyperalgesia (C) and motor functions (D) as in Figure 4. Data are means ± S.E.M. Comparison of the results with ANOVA revealed statistically significant differences between Grn−/− and wild-type mice for the percentage change of mechanical, cold and heat nociception and for the RotaRod running time as indicated with asterisks (P < 0.05).

Mentions: siRNAs sometimes can have off-target effects [26]. To confirm that observed intensified nociception and impaired motor function recovery after injury directly resulted from a PGRN-deficiency, we then tested mice with homozygous Grn gene deletion. Adult PGRN knockout mice and their age- and sex-matched wild-type controls were subjected to SNI, and compared for their responses to mechanical or cold allodynia (Fig. 5A and B), heat hyperalgesia (Fig. 5C) and performance in the RotaRod test (Fig. 5D). The baseline nociceptive sensitivity and RotaRod running performance did not differ between PGRN-deficient and wild-type mice. Their nociceptive behaviour in the first 2 weeks after SNI was also similar. However PGRN-deficient mice developed stronger sensitivity to mechanical (Fig. 5A), cold (Fig. 5B) and heat stimulation (Fig. 5C) than wild-type mice starting about 3 weeks after the nerve injury. The differences persisted and escalated towards the end the observation period, when these mice were 6–7 months old. Statistically, nociceptive sensitivity after SNI was enhanced in PGRN-deficient mice for mechanical (F11.8, df1, P = 0.0009), heat (F4.07, df1, P = 0.0464) and cold (F13.6, df1, P = 0.0004) stimulation (Fig. 5) as compared with wild-type controls. In addition, motor function recovery after SNI was significantly impaired in PGRN-deficient mice (Fig. 5D). Wild-type mice recovered their motor function one week after the injury, whereas the recovery of the PGRN-deficient mice only reached 50% and became worse seven weeks after injury. ANOVA for repeated measurements revealed significant differences between the two genotypes (F12.71, df1, P = 0.0006).


Progranulin contributes to endogenous mechanisms of pain defense after nerve injury in mice.

Lim HY, Albuquerque B, Häussler A, Myrczek T, Ding A, Tegeder I - J. Cell. Mol. Med. (2012)

Progranulin-deficient (Grn−/−) mice showed stronger nociceptive sensitivity after nerve injury than wild-type mice. PGRN knockout (Grn−/−) mice and their wild-type control mice (n = 8 per group, four male, four female, 10–12 weeks at the time of surgery) were tested for their mechanical allodynia (A), cold allodynia (B), heat hyperalgesia (C) and motor functions (D) as in Figure 4. Data are means ± S.E.M. Comparison of the results with ANOVA revealed statistically significant differences between Grn−/− and wild-type mice for the percentage change of mechanical, cold and heat nociception and for the RotaRod running time as indicated with asterisks (P < 0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3822842&req=5

fig05: Progranulin-deficient (Grn−/−) mice showed stronger nociceptive sensitivity after nerve injury than wild-type mice. PGRN knockout (Grn−/−) mice and their wild-type control mice (n = 8 per group, four male, four female, 10–12 weeks at the time of surgery) were tested for their mechanical allodynia (A), cold allodynia (B), heat hyperalgesia (C) and motor functions (D) as in Figure 4. Data are means ± S.E.M. Comparison of the results with ANOVA revealed statistically significant differences between Grn−/− and wild-type mice for the percentage change of mechanical, cold and heat nociception and for the RotaRod running time as indicated with asterisks (P < 0.05).
Mentions: siRNAs sometimes can have off-target effects [26]. To confirm that observed intensified nociception and impaired motor function recovery after injury directly resulted from a PGRN-deficiency, we then tested mice with homozygous Grn gene deletion. Adult PGRN knockout mice and their age- and sex-matched wild-type controls were subjected to SNI, and compared for their responses to mechanical or cold allodynia (Fig. 5A and B), heat hyperalgesia (Fig. 5C) and performance in the RotaRod test (Fig. 5D). The baseline nociceptive sensitivity and RotaRod running performance did not differ between PGRN-deficient and wild-type mice. Their nociceptive behaviour in the first 2 weeks after SNI was also similar. However PGRN-deficient mice developed stronger sensitivity to mechanical (Fig. 5A), cold (Fig. 5B) and heat stimulation (Fig. 5C) than wild-type mice starting about 3 weeks after the nerve injury. The differences persisted and escalated towards the end the observation period, when these mice were 6–7 months old. Statistically, nociceptive sensitivity after SNI was enhanced in PGRN-deficient mice for mechanical (F11.8, df1, P = 0.0009), heat (F4.07, df1, P = 0.0464) and cold (F13.6, df1, P = 0.0004) stimulation (Fig. 5) as compared with wild-type controls. In addition, motor function recovery after SNI was significantly impaired in PGRN-deficient mice (Fig. 5D). Wild-type mice recovered their motor function one week after the injury, whereas the recovery of the PGRN-deficient mice only reached 50% and became worse seven weeks after injury. ANOVA for repeated measurements revealed significant differences between the two genotypes (F12.71, df1, P = 0.0006).

Bottom Line: Knockdown of progranulin reduced the survival of dissociated primary neurons and neurite outgrowth, whereas addition of recombinant progranulin rescued primary dorsal root ganglia neurons from cell death induced by nerve growth factor withdrawal.Thus, up-regulation of progranulin after neuronal injury may reduce neuropathic pain and help motor function recovery, at least in part, by promoting survival of injured neurons and supporting regrowth.A deficiency in this mechanism may increase the risk for injury-associated chronic pain.

View Article: PubMed Central - PubMed

Affiliation: Pharmazentrum frankfurt, ZAFES, Clinical Pharmacology, Goethe-University, Frankfurt, Germany.

Show MeSH
Related in: MedlinePlus