Low-Level Laser Therapy Effectively Prevents Secondary Brain Injury Induced by Immediate Early Responsive Gene X-1 Deficiency

Abstract

A mild insult to the brain can sometimes trigger secondary brain injury, causing severe postconcussion syndrome, but the underlying mechanism is ill understood. We show here that secondary brain injury occurs consistently in mice lacking immediate early responsive gene X-1 (IEX-1), after a gentle impact to the head, which closely simulates mild traumatic brain injury in humans. The pathologic lesion was characterized by extensive cell death, widespread leukocyte infiltrates, and severe tissue loss. On the contrary, a similar insult did not induce any secondary injury in wild-type mice. Strikingly, noninvasive exposure of the injured head to a low-level laser at 4 hours after injury almost completely prevented the secondary brain injury in IEX-1 knockout mice. The low-level laser therapy (LLLT) suppressed proinflammatory cytokine expression like interleukin (IL)-1b and IL-6 but upregulated TNF-a. Moreover, although lack of IEX-1 compromised ATP synthesis, LLLT elevated its production in injured brain. The protective effect of LLLT may be ascribed to enhanced ATP production and selective modulation of proinflammatory mediators. This new closed head injury model provides an excellent tool to investigate the pathogenesis of secondary brain injury as well as the mechanism underlying the beneficial effect of LLLT.

Low-Level Light in Combination with Metabolic Modulators for Effective Therapy of Injured Brain

“…[26][27][28] The ability of sustaining mitochondrial functions in the injured brain may account for the benefit of LLL in TBI management showed recently. 12,17,28 The current investigations further validate that LLL stimulates ATP production and suppresses ROS generation in hypoxic cells and brain tissue. Hypoxia increases cytochrome c release from mitochondria.…”

“…Our previous investigations showed that mice bearing inadequate activity of mitochondria as a sequel of IEX-1 null mutation were prone to secondary brain injury. 17 The observation stresses an importance of mitochondrial activity in protection against secondary brain damage, which is highly anticipated, because neurons are one of the most oxygensensitive cells. Damage of blood vessels, in particular, capillary, occurs frequently at the site of injured brain, which disrupts oxygen supply and reduces cerebral blood flow drastically.…”

“…15 Our previous investigation showed that mice lacking immediate early responsive gene X-1 (IEX-1) were more susceptible to secondary brain injury than their wild-type littermates, because the null mutation of IEX-1 adversely affected mitochondrial functions and therefore diminished ATP formation in the injured brain. 16,17 Interestingly, noninvasive LLL illumination robustly enhanced ATP generation in injured brains of IEX-1 knockout mice. The enhancement was correlated positively and proportionally with LLL-mediated protection against secondary brain injury in the mice, suggesting a key role for mitochondria in both the pathogenesis of secondary brain injury and the effectiveness of LLL.…”

“…17 We first subjected neuronal SH-SY5Y cells to hypoxia by inclusion of CoCl 2 in the medium. This hypoxic mimetic compound-induced hypoxia and the expression of hypoxia-inducible factor 1α significantly (data not shown).…”

Transcranial Low-Level Laser (Light) Therapy for Brain Injury

“…The mechanism behind these series of events is not well understood. Zhang et al 65 showed that secondary brain ) with a spot size of 0.78 cm 2 in either CW, PW 10 Hz, or PW 100 Hz modes. Results are expressed as mean -SEM **p < 0.01 and ***p < 0.001 versus the other conditions.…”