Alpha-Lipoic Acid Ameliorates Radiation-Induced Salivary Gland Injury by Preserving Parasympathetic Innervation in Rats

Abstract

Radiation therapy is a standard treatment for patients with head and neck cancer. However, radiation exposure to the head and neck induces salivary gland (SG) dysfunction. Alpha lipoic acid (ALA) has been reported to reduce radiation-induced toxicity in normal tissues. In this study, we investigated the effect of ALA on radiation-induced SG dysfunction. Male Sprague–Dawley rats were assigned to the following treatment groups: control, ALA only (100 mg/kg, intraperitoneally), irradiation only, and ALA administration 24 h or 30 min prior to irradiation. The neck area, including SGs, was irradiated evenly at 2 Gy/min (total dose, 18 Gy) using a photon 6 MV linear accelerator. The rats were sacrificed at 2, 6, 8, and 12 weeks after irradiation. Radiation decreased SG weight, saliva secretion, AQP5 expression, parasympathetic innervation (GFRα2 and AchE expression), regeneration potentials (Shh and Ptch expression), salivary trophic factor levels (brain-derived neurotrophic factor and neurturin), and stem cell expression (Sca-1). These features were restored by treatment with ALA. This study demonstrated that ALA can rescue radiation-induced hyposalivation by preserving parasympathetic innervation and regenerative potentials.

Radiation-Induced Salivary Gland Dysfunction: Mechanisms, Therapeutics and Future Directions

“…Treatment with NRTN has been shown to enhance parasympathetic innervation and reduce epithelial apoptosis post-IR, consistent with increased end bud formation within SMGs, supporting a potential regenerative role for neurotrophic signaling in the repair of IR-induced salivary gland damage [ 53 ]. Rats administered 18 Gy IR exhibit reduced levels of the neurotrophic factors brain-derived neurotrophic factor (BDNF) and NTRN as well as decreased levels of the neurotrophic factor receptor, GRFα2, acetylcholinesterase and neurofilament staining in SMGs, which could be reversed with α-lipoic acid treatment [ 70 ]. In minipigs following 20 Gy IR, there is a reduction in levels of BDNF, NTRN, acetylcholinesterase and the acetylcholine receptor, Chrm1, indicative of decreased parasympathetic innervation, responses that can be reversed with intraglandular adenoviral delivery of Shh at 4 weeks post-IR [ 52 ].…”

“…During the transition phase, loss of apical/basolateral polarity as a result of PKCζ inactivation [ 55 , 62 , 63 ], increases nuclear Yes-associated protein (Yap) levels [ 55 , 64 ], compensatory proliferation [ 62 , 65 , 66 ], cellular senescence [ 60 , 67 , 68 ], and cytoskeletal rearrangements [ 50 , 69 ], which contribute to long-term dysfunction. Changes in innervation and vasculature have been reported as early as 24 h post-IR [ 53 ], as well as at chronic time points [ 54 , 70 ]. Though inconsistently reported, fibrosis generally appears between 4 and 6 months following irradiation [ 1 , 44 , 71 ].…”

Insight into Salivary Gland Aquaporins

“…The loss of AQP5 expression could participate in the development of severe xerostomia in patients undergoing radiotherapy. Rat submandibular glands subjected to a low-dose radiation displayed decreased AQP5 expression [ 96 , 97 , 98 ] and impaired AQP5 trafficking [ 99 ], as compared to the sham-irradiated animals. Radiation treatment of organotypic cultures from mice SG showed a time-dependent decrease in AQP5 expression [ 100 ].…”

“…Long-term administration of pilocarpine to irradiated mice has a beneficial effect in terms of saliva secretion [ 102 ]. Alpha-lipoic acid also rescued radiation-induced SG hypofunction in rats [ 97 ].…”

Experimental Animal Model Systems for Understanding Salivary Secretory Disorders

“…Another study revealed that, after irradiation, TRPM2 −/− mice displayed only transient loss of STIM1 and Store-operated Ca2+ entry (SOCE) along with transient hyposalivation and, moreover, gene therapy to express STIM1 increased the salivary flow and SOCE [ 40 ]. Collectively, recent studies showed that irradiation of the salivary gland was accompanied by extensive deterioration including decreased AQP5 expression, parasympathetic innervation (GFRα2 and AchE expression), regeneration potentials (Shh and Ptch expression), salivary trophic factor levels (brain-derived neurotrophic factor and neurturin), and stem cell expression (Sca-1) [ 44 ].…”