Compositions and methods for treating non-hemorrhagic closed head injury

Inventors

Zeligs, Michael A. • Jacobs, Irwin C.

Assignees

Boulder Bioscience LLC

Abstract

Provided herein are methods of treating non-hemorrhagic closed head injury (NHCHI) with 3,3′-diindolylmethane or an analog thereof. In one embodiment, NHCHI covers Traumatic Brain Injuries (TBIs) including mild to severe concussion, blast injury due to proximity to explosions, cerebral contusion, coup-contrecoup injury, DAI, Second Impact Syndrome, or CHI associated with deceleration injury.

Core Innovation

The invention relates to treating non-hemorrhagic closed head injury (NHCHI) and traumatic brain injury (TBI) by administering 3,3′-diindolylmethane (DIM) and, in some embodiments, DIM analogs. The described approach targets the acute-phase response (APR) and extracellular vesicle (EV)-driven neuroinflammation, and is reported to improve neurobehavioral outcomes in NHCHI/TBI contexts.

The problem addressed is the occurrence of NHCHI/TBI, including concussion/mild TBI, cerebral contusion, coup-contrecoup injury, and diffuse axonal injury (DAI), which can lead to increased inflammatory activity and detrimental neurobehavioral consequences. The disclosure frames the need to reduce acute-phase response and EV-driven neuroinflammation in non-hemorrhagic settings, including evaluation by imaging to rule out intracranial hemorrhage.

The methods encompass administering DIM in relation to timing after injury and in clinically characterized patient settings, including early after injury and conditions such as severe consciousness status where imaging may be used to support appropriate patient selection. Administration routes described include oral self-microemulsifying drug delivery system (SMEDDS), intravenous (IV) premix, and direct-to-CSF approaches using lumbar puncture or a sub-arachnoid catheter, and the disclosure also describes combination treatment with second active agents.

The disclosure further identifies formulation and analogs such as HB-237, LTR, and indole-3-carbinol, and presents co-administration including DIM with mannitol for preventing or limiting an increase in intracranial pressure. Translational efficacy is described using murine and rat efficacy narratives associated with reduced edema, reduced circulating EV numbers, improved sensorimotor performance and memory/fear conditioning, and reduced histopathology.

Claims Coverage

The provided independent claims cover two inventive methods: treating NHCHI by administering DIM, optionally with a second active agent, and preventing or limiting increased intracranial pressure in NHCHI by co-administering DIM and mannitol. Across the independent claim set, the coverage centers on DIM-based treatment of NHCHI and one DIM–mannitol co-administration for intracranial pressure control.

The claim coverage is grounded on DIM-based treatment of NHCHI, with optional inclusion of a second active agent in the general treatment method and a specifically recited DIM–mannitol co-administration for preventing or limiting increased intracranial pressure.

Stated Advantages

Documented Applications