Traumatic Brain Injury as a Potential Risk Factor for Diabetes Mellitus in the Veteran Population.

This review examines various aspects of traumatic brain injury (TBI) and its potential role as a causative agent for type 2 diabetes mellitus (T2DM) in the veteran population. The pituitary glands and the hypothalamus, both housed in the intracranial space, are the most important structures for the homeostatic regulation of almost every hormone in the human body. As such, TBI not only causes psychological and cognitive impairments but can also disrupt the endocrine system.

Neurocognitive Outcomes in a Cisternal Blood Injection Murine Model of Subarachnoid Hemorrhage.

Background: Subarachnoid hemorrhage (SAH) results in neurocognitive dysfunction and anxiety in humans and in animal models. Neurobehavioral tests such as the Morris Water Maze (MWM) and Elevated Plus Maze (EPM) tests are validated in several models of SAH but have not been tested in the murine cisternal blood injection SAH model.

Methods: Adult C57BL/6 mice (n=16) were randomized into two groups.

Stroke-Induced Peripheral Immune Dysfunction in Vitamin D-Deficient Conditions: Modulation by Progesterone and Vitamin D.

Vitamin D deficiency (D) alters morphology and outcomes after a stroke. We investigated the interaction of D following post-stroke systemic inflammation and evaluated whether administration of progesterone (P) or vitamin D (D) will improve outcomes. D rats underwent stroke with lipopolysaccharide (LPS)-induced systemic inflammation.

Post-ischemic stroke systemic inflammation: Immunomodulation by progesterone and vitamin D hormone.

Post-stroke systemic inflammation, due to the injury itself and exacerbated by in-hospital infections, can increase morbidity and mortality in stroke patients. In this study, we examined the immunomodulatory effects of progesterone (P4) alone and in combination with vitamin D hormone (VDH) on acute phase post-stroke peripheral immune dysfunction and functional/behavioral deficits. Adult rats underwent transient middle cerebral artery occlusion/reperfusion (tMCAO) and delayed systemic inflammation was induced by injections of lipopolysaccharide (LPS) beginning 24 h post-stroke.

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy following Ischemic Brain Injury.

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress.

Effect of Progesterone on Cerebral Vasospasm and Neurobehavioral Outcomes in a Rodent Model of Subarachnoid Hemorrhage.

Background: Subarachnoid hemorrhage (SAH) induces widespread inflammation leading to cellular injury, vasospasm, and ischemia. Evidence suggests that progesterone (PROG) can improve functional recovery in acute brain injury owing to its anti-inflammatory and neuroprotective properties, which could also be beneficial in SAH. We hypothesized that PROG treatment attenuates inflammation-mediated cerebral vasospasm and microglial activation, improves synaptic connectivity, and ameliorates functional recovery after SAH.

Progesterone improves neurocognitive outcomes following therapeutic cranial irradiation in mice.

Despite improved therapeutic methods, CNS toxicity resulting from cancer treatment remains a major cause of post-treatment morbidity. More than half of adult patients with cranial irradiation for brain cancer develop neurobehavioral/cognitive deficits that severely impact quality of life. We examined the neuroprotective effects of the neurosteroid progesterone (PROG) against ionizing radiation (IR)-induced neurobehavioral/cognitive deficits in mice.

Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone.

Despite the fact that stress is associated with increased risk of stroke and worsened outcome, most preclinical studies have ignored this comorbid factor, especially in the context of testing neuroprotective treatments. Preclinical research suggests that stress primes microglia, resulting in an enhanced reactivity to a subsequent insult and potentially increasing vulnerability to stroke. Ischemia-induced activated microglia can be polarized into a harmful phenotype, M1, which produces pro-inflammatory cytokines, or a protective phenotype, M2, which releases anti-inflammatory cytokines and neurotrophic factors.

Progesterone modulates diabetes/hyperglycemia-induced changes in the central nervous system and sciatic nerve.

We investigated the effect of progesterone (P4) treatment on diabetes/hyperglycemia-induced pathological changes in brain, spinal cord and sciatic nerve tissue in male rats. Animals were rendered hyperglycemic by a single dose of streptozotocin (STZ). P4 treatment was started after hyperglycemia was confirmed and body weight and blood glucose levels were monitored once/week for 5weeks.

Neuroprotection by progesterone after transient cerebral ischemia in stroke-prone spontaneously hypertensive rats.

We investigated the neuroprotective effects of progesterone (P4) treatment in stroke-prone spontaneously hypertensive rats (SHRSPs) given 60-min transient middle cerebral artery occlusion (tMCAO). The treatment groups were: (1) Wistar-Kyoto (normotensive sham), (2) SHRSP (hypertensive sham), (3) tMCAO SHRSPs (SHRSP+tMCAO), and (4) SHRSP+tMCAO+P4. P4 (8mg/kg) was administered 1h after occlusion and then daily for 14days.

Progesterone in the treatment of neonatal arterial ischemic stroke and acute seizures: Role of BDNF/TrkB signaling.

Neonatal stroke is among the top ten causes of childhood death and permanent disability in survivors, but no safe and effective acute treatments exist. To advance understanding of its neuroprotective mechanisms, we examined the effects of progesterone (PROG) on local and systemic inflammation (IL-1β, IL-6, TNFα), brain derived neurotrophic factor/Tropomyosin receptor kinase B (BDNF/TrkB) signaling, vascular damage (vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9)), acute behavioral seizures and brain infarction size following neonatal arterial ischemic stroke in mice. CD1 mouse pups (postnatal day 12, mixed gender) received permanent unilateral right common carotid ligation (pUCCL) or sham surgery.

The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells.

Glioblastoma multiforme (GBM) is the most common and most aggressive malignant brain tumor. Despite optimal treatment and evolving standard of care, the median survival of patients diagnosed with GBM is only 12-15 months. In this study, we combined progesterone (PROG) and temozolomide (TMZ), a standard chemotherapeutic agent for human GBM, to test whether PROG enhances the antitumor effects of TMZ and reduces its side effects.

Progesterone and vitamin D combination therapy modulates inflammatory response after traumatic brain injury.

Objective: Inflammation is an important component of the response to traumatic brain injury (TBI). Progesterone has been shown to inhibit neuroinflammation following (TBI) and may do so through Toll-like receptor (TLR)-mediated pathways. In vitro studies indicate that 1,25-dihydroxyvitamin D(3) (VDH) may also modulate the inflammatory response through the TLR4 pathway.

Long-term behavioral deficits and recovery after transient ischemia in middle-aged rats: Effects of behavioral testing.

Purpose: Most pre-clinical stroke studies address the acute phase after injury, with less attention to long-term effects of injury, treatment, and experimental testing itself. We addressed these questions: 1) Will functional deficits persist up to 8 weeks following transient stroke in older animals? 2) Will functional deficits resolve spontaneously, with time and/or repeated behavioral testing?

Methods: Male Sprague-Dawley rats (12 months) were pre-trained on behavioral tasks to provide baseline data and then underwent transient middle artery occlusion (tMCAO) or sham surgery. We measured motor, sensory, cognitive and gait impairments over 8 weeks, and the extent of hemispheric brain infarction.

Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling.

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with a mean patient survival of 13-15 months despite surgical resection, radiation therapy and standard-of-care chemotherapy. We investigated the chemotherapeutic effects of the hormone progesterone (P4) on the growth of human GBM in four genetically different cell lines (U87MG, U87dEGFR, U118MG, LN-229) in vitro and in a U87MG subcutaneous xenograft mouse model. At high concentrations (20, 40, and 80 μM), P4 significantly (P<0.

Progesterone in transient ischemic stroke: a dose-response study.

Rationale: Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose-response study in a transient ischemic stroke model is lacking.

Objectives: We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats.

Methods: Cerebral ischemia was induced in 13-month-old male Sprague-Dawley rats by right middle cerebral artery occlusion for 2 h followed by reperfusion.

Delayed progesterone treatment reduces brain infarction and improves functional outcomes after ischemic stroke: a time-window study in middle-aged rats.

We evaluated the neuroprotective effects of delayed progesterone (PROG) treatment against ischemic stroke-induced neuronal death, inflammation, and functional deficits. We induced transient focal cerebral ischemia in male rats and administered PROG (8 mg/kg) or vehicle intraperitoneally at 3, 6, or 24 hours post occlusion, subcutaneously 5 hours later and then every 24 hours for 7 days. Behavioral outcomes were evaluated over 22 days.

Progesterone and vitamin D: Improvement after traumatic brain injury in middle-aged rats.

Progesterone (PROG) and vitamin D hormone (VDH) have both shown promise in treating traumatic brain injury (TBI). Both modulate apoptosis, inflammation, oxidative stress, and excitotoxicity. We investigated whether 21 days of VDH deficiency would alter cognitive behavior after TBI and whether combined PROG and VDH would improve behavioral and morphological outcomes more than either hormone alone in VDH-deficient middle-aged rats given bilateral contusions of the medial frontal cortex.

Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection.

We investigated whether combinatorial post-injury treatment with progesterone (P4) and vitamin D hormone (VDH) would reduce ischemic injury more effectively than P4 alone in an oxygen glucose deprivation (OGD) model in primary cortical neurons and in a transient middle cerebral artery occlusion (tMCAO) model in rats. In the OGD model, P4 and VDH each showed neuroprotection individually, but combination of the "best" doses did not show substantial efficacy; instead, the lower dose of VDH in combination with P4 was the most effective. In the tMCAO model, P4 and VDH were given alone or in combination at different times post-occlusion for 7 days.

Neuroprotective effects of Tacrolimus (FK-506) and Cyclosporin (CsA) in oxidative injury.

The detrimental effects of hypoxic damage to central nervous system lead to energy depletion, free radical formation, lipid peroxidation (LPO), and increased calcium. We hypothesized that in vitro tacrolimus (FK-506) and cyclosporine A (CsA) could be protective against hypoxic damage in spinal cord. Dorsal columns were isolated from the spinal cord of adult rats and injured by exposure to hypoxic condition for 1 h, and treated with FK-506 (0.

Progesterone inhibits the growth of human neuroblastoma: in vitro and in vivo evidence.

We investigated the antitumorogenic effects of progesterone (P4) in a human neuroblastoma (SK-N-AS) cell line in vitro and in a mouse xenograft model of neuroblastoma. The safety of P4 was tested in rat primary cortical neurons and human foreskin fibroblasts (HFF-1). At high doses, P4 significantly (P < 0.