Differential effects of early postinjury treatment with neuroprotective drugs in a mouse model using diffuse reflectance spectroscopy

Abstract

Abstract. The time required for the arrival of an ambulance crew and administration of first aid is critical to clinical outcome, particularly in the case of head injury victims requiring neuroprotective drugs following a car accident, falls, and assaults. Short response times of the medical team, together with proper treatment, can limit injury severity and even save a life before transportation to the nearest medical center. We present a comparative evaluation of five different neuroprotective drugs frequently used in intensive care and operating units in the early phase following traumatic brain injury (TBI): hypertonic saline (HTS), mannitol, morphine, melatonin, and minocycline. The effectiveness of these drugs in terms of changes in brain tissue morphology (cell organelle size, density, distribution, etc.) and biochemical tissue properties (chromophores' content) was experimentally evaluated through analysis of the spectral reduced scattering and optical absorption coefficient parameters in the near-infrared (NIR) optical range (650 to 1000 nm). Experiments were conducted on anesthetized male mice subjected to a noninvasive closed head weight-drop model of focal TBI (n ¼ 50 and n ¼ 10 control) and monitored using an NIR diffuse reflectance spectroscopy system utilizing independent source-detector separation and location. After 10 min of baseline measurement, focal TBI was induced and measurements were conducted for 20 min. Subsequently, a neuroprotective drug was administrated and measurements were recorded for another 30 min. This work's major findings are threefold: first, minocycline was found to improve hemodynamic outcome at the earliest time postinjury. Second, HTS decreased brain water content and inhibited the increase in intracranial pressure. Third, the efficacy of neuroprotective drugs can be monitored noninvasively with diffuse reflectance spectroscopy. The demonstrated ability to noninvasively detect cerebral physiological properties following early administration of neuroprotective drugs underlines the need for more extensive investigation of the combined use of clinical drugs in larger-scale preclinical experiments to find the most beneficial drug treatment for brain injury patients.

Melatonin as a Therapy for Traumatic Brain Injury: A Review of Published Evidence

“…The global interest in evaluating the therapeutic effects of MEL after TBI is evident by the worldwide research conducted on this topic, including 8 studies from Turkey [ 20 , 24 , 29 , 30 , 31 , 32 , 33 , 34 ], 4 from the United States [ 35 , 36 , 37 ], 3 from China [ 38 , 39 ], 2 from Iran [ 40 , 41 ], 2 from Israel [ 42 , 43 ], 1 from France [ 44 ], 1 from Germany [ 44 ], and 1 from Italy [ 45 ].…”

“…Several different injury models were used to garner evidence regarding the therapeutic effects of MEL after TBI. Most commonly used was weight drop injury, which was employed in 12 of the studies [ 20 , 24 , 29 , 30 , 31 , 32 , 33 , 38 , 41 , 42 , 43 , 44 ]. Of the studies using weight drop, several methods and modifications were used including: Marmarou’s model, Feeney’s model, and Marklund’s model.…”

“…Some of the studies tested multiple doses of MEL or several dosing schedules [ 20 , 24 , 33 , 35 , 39 , 40 , 41 , 48 ]. A small number of studies compared the effects of MEL to another drug with known neuroprotective (e.g., anti-oxidant) properties [ 20 , 42 , 43 ]. Five studies tested the effects of MEL in combination with another drug [ 34 , 38 , 45 , 46 ].…”

“…Commonly, a bell-shaped curve was reported with the middle dose, conferring benefit, and low and high doses ineffective [ 43 , 44 ]. Notably, the effective doses differed, with one study finding 1.25 mg/kg of MEL (but not 0.625 mg/kg or 2.5 mg/kg) effective [ 44 ], and another study finding 5 mg/kg (not 1 mg/kg or 10 mg/kg) effective [ 43 ]. Moreover, some of the regimens studied actually compounded the deleterious effects of injury.…”

Noninvasive assessment of hemodynamic and brain metabolism parameters following closed head injury in a mouse model by comparative diffuse optical reflectance approaches

“…The calibration and validation of this technique was detailed previously, based on reference tissue-simulating phantom experiments with known optical properties. 57 In contrast to the above structured illumination technique, we use here 500 wavelengths, which dramatically increase our spectral resolution and, therefore, the accuracy of the results. This is currently achieved at the expense of the field of vision imaged, since single-point measurements cannot provide spatial information.…”