Traumatic brain injury (TBI) is a major public health problem. Each year in the US: ~270,000 people experience a moderate or severe TBI, ~50,000 people die from head injury, ~230,000 people are hospitalized for TBI and survive, and ~80,000 of these survivors have significant injury-related disabilities. Dependent upon the severity of the TBI, chronic deficits in cognitive and motor function can result. Recovery from a severe TBI may take months and years, and in many cases function does not return to normal. Thus, there is a desperate need for new therapies that function to completely restore brain function. The spontaneous, although often incomplete, cognitive recovery that occurs following TBI is thought to involve neuroregeneration that includes neurogenesis (4). Indeed, the heightened proliferative response of neural stem cells (NSC) and their anatomical integration in the hippocampus following injury strongly indicates neurogenesis as an important component of recovery following TBI. Our and other recent data indicate that gonadotropins and progestagens are key neurohormones that promote neurogenesis in the brain during both embryogenesis and adulthood. Specifically, the gonadotropin hormones human chorionic gonadotropin (hCG) and its adult equivalent luteinizing hormone (LH), which act rapidly to upregulate progesterone (P4) synthesis (10), are central to neurogenesis. However, the stress from a TBI has been shown to markedly suppress circulating gonadotropin and sex steroid concentrations. Moreover, there is indirect evidence that the actions of these hormones are compromised following TBI, since the rampant oxidative stress associated with TBI inhibits steroidogenic enzyme function, leading to a neurosteroid deficient state. We therefore hypothesize that the chronic treatment of TBI patients with neurohormones known to induce neurogenesis in the adult brain would act to enhance functional recovery. The migration of newborn neurons from the dentate gyrus into cornu ammonis regions of the hippocampus to reestablish connectivity takes months. Therefore, in this pilot study we will assess the effects of chronic treatments of hCG and P4 post-TBI on: 1) promoting neurogenesis (Aim 1), and 2) functional recovery (Aim 2).
Specific Aim 1 will test the efficacy of hCG and P4 in enhancing neurogenesis in a rat model of TBI. Male Sprague-Dawley rats at 3 months of age will be subjected to sham surgery or a cortical contusion injury (CCI). After 3-months, rat will then be treated with vehicle, hCG, or P4 for 6 months and neurogenesis examined using double immunofluorescence against a marker of cell division (5-ethynyl-2'-deoxyuridine; EdU) and neuron phenotype (NeuN). To confirm the neurogenic potential of hCG and P4, separate groups of rats will be treated for 6-months with the GnRH superagonist leuprolide acetate (a gonadotropin antagonist) or the progesterone receptor antagonist ORG-31710, 3-months post-TBI. Cell death, lesion size and plasma and brain hormone status will be measured.
In Specific Aim 2, the rats described in specific Aim 1 will be assessed for cognitive, behavioral and motor skills every 3 months. Tests for specific cognitive, behavioral and motor functions will include: 1 general examination of gross neurologic function, 2) Morris water maze (tests of spatial learning), and 3) tests of motor coordination and ataxia. Treatments will be correlated with neurogenesis, neuropathological measures, brain function, and plasma and brain hormone status. The neurohormones described above are the physiological hormones that promote cell proliferation and differentiation during neurogenesis in the embryo, fetus and adult brain. The experiments in this proposal will determine whether neurohormones promote neurogenesis and functional improvements in the recovering TBI brain. Availability of a safe, low-cost, readily available therapy that limits TBI-induced neurodegeneration and promotes the body's innate repair mechanisms would have a dramatic impact on both the short- and long-term cognitive rehabilitation of individuals following a TBI.
Traumatic brain injury is a 'silent epidemic' that affects an estimated 2-6 million Americans, and for which there are no effective treatments. This proposal will test if human chorionic gonadotropin, a hormone that promotes the formation of new neurons, enhances cognitive recovery following a traumatic brain injury.
|Geddes, Rastafa I; Hayashi, Kentaro; Bongers, Quinn et al. (2017) Conjugated Linoleic Acid Administration Induces Amnesia in Male Sprague Dawley Rats and Exacerbates Recovery from Functional Deficits Induced by a Controlled Cortical Impact Injury. PLoS One 12:e0169494|