Secondary hypoxic/ischemic injuries, stemming from reductions in cerebral blood flow are important contributing factors in progressive neuronal dysfunction after brain trauma. A greater preclinical understanding of how brain trauma leads to secondary hypoxia/ischemia is necessary in the development of posttraumatic brain injury (TBI) therapeutics. To this end, we examined the density of microvascular coverage in the injured and contralateral cortical hemispheres using two intensities of fluid percussion trauma in rats. A silicone microangiography technique showed a significant loss in microvascular density in 2 atmosphere (atm) (16.9 ± 3.8%) and 3 atm (15.7 ± 1.3%) injured animals relative to sham animals (29.9±2.5%; P < 0.01). RECA-1 immunohistochemistry indicated that capillary changes involved a reduction in capillary number and diameter. Reduction in microvascular density was shown to be a diffuse phenomenon occurring up to 4 mm rostral and caudal to the injury epicenter. Recovery of microvasculature occurred by 2 weeks after injury only in the 2 atm injury group. Expression of HIF1a and increased vascular endothelial growth factor expression were observed in the ipsilateral hippocampus suggesting sufficiently impaired microcirculation resulting in the expression of hypoxic-response proteins. Collectively, the results indicate diffuse and heterogeneous microvascular alterations as well as endogenous expression of neuroprotective and neovascularization pathways after TBI.

Vascular endothelial growth factor (VEGF) plays a role in angiogenesis and has been shown to be neuroprotective following central nervous system trauma. In the present study we evaluated the pro-angiogenic and neuroprotective effects of an engineered zinc-finger protein transcription factor transactivator targeting the vascular endothelial growth factor A (VEGF-ZFP). We used two virus delivery systems, adeno-virus and adeno-associated virus, to examine the effects of early and delayed VEGF-A upregulation after brain trauma, respectively. Male Sprague-Dawley rats were subject to a unilateral fluid percussion injury (FPI) of moderate severity (2.2-2.5 atm) followed by intracerebral microinjection of either adenovirus vector (Adv) or an adeno-associated vector (AAV) carrying the VEGF-ZFP construct. Adv-VEGF-ZFP-treated animals had significantly fewer TUNEL positive cells in the injured penumbra of the cortex (p<0.001) and hippocampus (p=0.001) relative to untreated rats at 72 h post-injury. Adv-VEGF-ZFP treatment significantly improved fEPSP values (p=0.007) in the CA1 region relative to injury alone. Treatment with AAV2-VEGF-ZFP resulted in improved post-injury microvascular diameter and improved functional recovery on the balance beam and rotarod task at 30 days post-injury. Collectively, the results provide supportive evidence for the concept of acute and delayed treatment following TBI using VEGF-ZFP to induce angiogenesis, reduce cell death, and enhance functional recovery.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome (MT-TL1 gene) is a progressive neurologic disorder with stroke-like episodes (SLEs), which are recurrent neurologic deficits resembling vasoocclusive strokes. 1 However, SLEs are not restricted to vascular territories and have a predilection for the occipital and posterior parietal and temporal cortices, 2 may evolve subacutely over hours to days, 3 and have greater potential for reversibility. 4 Their pathophysiology is incompletely understood. Current literature suggests a combination of neuronal mitochondrial energy failure and cerebrovascular angiopathy with dysregulated perfusion. 5 Recent work has demonstrated a beneficial effect of L-arginine in MELAS for acute treatment and prevention of SLEs, 6 and a relative serum arginine deficiency in patients with MELAS at baseline with a further decrease during SLEs. 6 The rationale was to utilize the vasodilatory properties of arginine through its conversion to nitric oxide; however, blood flow dysregulation in MELAS is complex involving both hypo-and hyperperfusion. Arginine is also a precursor for creatine, can be decarboxylated to agmatine (neurotransmitter), and can be converted to a-ketoglutarate, improving tricarboxylic acid cycle kinetics and cellular anaplerosis. 7Level of evidence. This study provides Class IV level of evidence. It is a single observational study without controls.Case report. A right-handed boy aged 10 years, 9 months presented with fever and upper respiratory tract infection followed by acute onset of headache, vomiting, change in mental status, right-sided focal seizures, and hemiparesis, which developed over 3 hours.He was born of normal pregnancy and term delivery with normal early development. Two years before presentation, he had an episode of fever and encephalopathy with left-sided focal seizures and left hemiparesis with right temporal lobe swelling on head CT and was treated for suspected herpes encephalitis with acyclovir (PCR was negative). He made a nearcomplete recovery with mild residual left leg weakness at discharge. At age 10 years, 2 months, he had a second episode of encephalopathy with right-sided focal seizures and negative virology and had a large area of abnormal high FLAIR (fluid-attenuated inversion recovery) signal in the left temporal lobe. At 3-month follow-up, he had memory, processing, and word-finding difficulties but no focal weakness or field defect.At presentation, he appeared confused and Glasgow Coma Scale score was 13. He had a receptive aphasia and a right superior quadrantanopia. His bilateral asymmetric ptosis, which had developed over 2 years, was worse with fatigue or illness. He had asthenic muscle bulk and a right hemiparesis.Brain MRI showed normal basal ganglia and high FLAIR signal in the left superior temporal gyrus (figure, A), and left parietal lobe with effacement of sulci (figure, B). Magnetic resonance spectroscopy showed a lactate peak at 1.33 ppm (figure, G). CSF lactate was elevated at 5.29 mM...