bryostatin-1 and Brain-Injuries

Recent wars in Iraq and Afghanistan have accounted for an estimated 270,000 blast exposures among military personnel. Blast traumatic brain injury (TBI) is the 'signature injury' of modern warfare. Blood brain barrier (BBB) disruption following blast TBI can lead to long-term and diffuse neuroinflammation. In this study, we investigate for the first time the role of bryostatin-1, a specific protein kinase C (PKC) modulator, in ameliorating BBB breakdown. Thirty seven Sprague-Dawley rats were used for this study. We utilized a clinically relevant and validated blast model to expose animals to moderate blast exposure. Groups included: control, single blast exposure, and single blast exposure + bryostatin-1. Bryostatin-1 was administered i.p. 2.5 mg/kg after blast exposure. Evan's blue, immunohistochemistry, and western blot analysis were performed to assess injury. Evan's blue binds to albumin and is a marker for BBB disruption. The single blast exposure caused an increase in permeability compared to control (t = 4.808, p < 0.05), and a reduction back toward control levels when bryostatin-1 was administered (t = 5.113, p < 0.01). Three important PKC isozymes, PKCα, PKCδ, and PKCε, were co-localized primarily with endothelial cells but not astrocytes. Bryostatin-1 administration reduced toxic PKCα levels back toward control levels (t = 4.559, p < 0.01) and increased the neuroprotective isozyme PKCε (t = 6.102, p < 0.01). Bryostatin-1 caused a significant increase in the tight junction proteins VE-cadherin, ZO-1, and occludin through modulation of PKC activity. Bryostatin-1 ultimately decreased BBB breakdown potentially due to modulation of PKC isozymes. Future work will examine the role of bryostatin-1 in preventing chronic neurodegeneration following repetitive neurotrauma.

Topics: Animals; Antigens, CD; Astrocytes; Blast Injuries; Blood-Brain Barrier; Brain Injuries; Bryostatins; Cadherins; Endothelial Cells; Male; Occludin; Prefrontal Cortex; Protein Kinase C-alpha; Protein Kinase C-delta; Protein Kinase C-epsilon; Rats; Rats, Sprague-Dawley; Tight Junctions; Zonula Occludens-1 Protein

Traumatic brain injury (TBI) is a frequent consequence of vehicle, sport and war related injuries. More than 90% of TBI patients suffer mild injury (mTBI). However, the pathologies underlying the disease are poorly understood and treatment modalities are limited. We report here that in mice, the potent PKC activator bryostatin1 protects against mTBI induced learning and memory deficits and reduction in pre-synaptic synaptophysin and post-synaptic spinophylin immunostaining. An effective treatment has to start within the first 8h after injury, and includes 5 × i.p. injections over a period of 14 days. The treatment is dose dependent. Exploring the effects of the repeated bryostatin1 treatment on the processing of the amyloid precursor protein, we found that the treatment induced an increase in the putative α-secretase ADAM10 and a reduction in β-secretase activities. Both these effects could contribute towards a reduction in β-amyloid production. These results suggest that bryostatin1 protects against mTBI cognitive and synaptic sequela by rescuing synapses, which is possibly mediated by an increase in ADAM10 and a decrease in BACE1 activity. Since bryostatin1 has already been extensively used in clinical trials as an anti-cancer drug, its potential as a remedy for the short- and long-term TBI sequelae is quite promising.

Topics: Animals; Antineoplastic Agents; Brain Injuries; Bryostatins; Disease Models, Animal; Enzyme Activation; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Protein Kinase C