Toll-Like Receptor 4 Plays a Significant Role in the Biochemical and Neurological Alterations Observed in Two Distinct Mice Models of Huntington's Disease.

Toll-like receptors (TLRs) are central players in innate immunity responses. They are expressed in glial cells and neurons, and their overactivation leads to the production of proinflammatory molecules, neuroinflammation, and neural damage associated with many neurodegenerative pathologies, such as Huntington's disease (HD). HD is an inherited disorder caused by a mutation in the gene coding for the protein Huntingtin (Htt). Expression of mutated Htt (mHtt) causes progressive neuronal degeneration characterized by striatal loss of GABAergic neurons, oxidative damage, neuroinflammatory processes, and impaired motor behavior. The main animal models to study HD are the intrastriatal injection of quinolinic acid (QA) and the transgenic B6CBA-Tg (HDexon1)61Gpb/1 J mice (R6/1). Those models mimic neuronal damage and systemic manifestations of HD. The objective of this work was to study the participation of TLR4 in the manifestations of neuronal damage and HD symptoms in the two mentioned models. For this purpose, C57BL6/J and TLR4-KO mice were administered with QA, and after that motor activity, and neuronal and oxidative damages were measured. R6/1 and TLR4-KO were mated to study the effect of low expression of TLR4 on the phenotype manifestation in R6/1 mice. We found that TLR4 is involved in motor activity, and neurological and oxidative damage induced by intrastriatal injection of QA, and the low expression of TLR4 causes a delay in the onset of phenotypic manifestations by the mHtt expression in R6/1 mice. Our results show that TLR4 is involved in both models of HD and focuses then as a therapeutic target for some deleterious reactions in HD.

Anion exchanger 3 in dorsal root ganglion contributes to nerve injury-induced chronic mechanical allodynia and thermal hyperalgesia.

OBJECTIVE: To determine the role of anion exchanger 3 (AE3) in dorsal root ganglion (DRG) in nerve injury-induced chronic nociception in the rat. METHODS: Spared nerve injury (SNI) was used to induce neuropathic pain. Von Frey filaments and Hargreaves test were used to assess tactile allodynia and thermal hyperalgesia, respectively. Drugs were given by intrathecal administration. Western blotting was used to determine AE3 expression in DRG. KEY FINDINGS: SNI produced long-lasting mechanical allodynia and thermal hyperalgesia. AE3 was found in DRG of sham-operated rats. SNI enhanced baseline AE3 expression in L4 and L5 DRGs at days 7 and 14, respectively. In contrast, SNI did not affect AE3 expression in L6 DRG. AE3 expression returned to baseline levels 21 days after SNI. Intrathecal 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) (5-50 µg) pretreatment prevented SNI-induced allodynia and, at a lesser extent, hyperalgesia. Moreover, DIDS (50 µg) reduced SNI-induced AE3 upregulation in L4, but not L5, DRGs. Intrathecal DIDS (5-50 µg) or anti-AE3 antibody (1 µg), but not vehicle, post-treatment (6 days) partially reversed SNI-induced allodynia and hyperalgesia. DIDS or anti-AE3 antibody post-treatment diminished SNI-induced AE3 upregulation in L4 and L5 DRGs. CONCLUSIONS: Data suggest that AE3 is present in DRG and contributes to mechanical allodynia and thermal hyperalgesia in neuropathic rats.