The blood-brain barrier (BBB) is formed by tightly connected cerebrovascular endothelial cells, but its normal function also depends on paracrine interactions between the brain endothelium and closely located glia. There is a growing consensus that brain injury, whether it is ischemic, hemorrhagic, or traumatic, leads to dysfunction of the BBB. Changes in BBB function observed after injury are thought to contribute to the loss of neural tissue and to affect the response to neuroprotective drugs. New discoveries suggest that considering the entire gliovascular unit, rather than the BBB alone, will expand our understanding of the cellular and molecular responses to traumatic brain injury (TBI). This review will address the BBB breakdown in TBI, the role of blood-borne factors in affecting the function of the gliovascular unit, changes in BBB permeability and post-traumatic edema formation, and the major pathophysiological factors associated with TBI that may contribute to post-traumatic dysfunction of the BBB. The key role of neuroinflammation and the possible effect of injury on transport mechanisms at the BBB will also be described. Finally, the potential role of the BBB as a target for therapeutic intervention through restoration of normal BBB function after injury and/or by harnessing the cerebrovascular endothelium to produce neurotrophic growth factors will be discussed.

/pdf/blood-brain-barrier-pathophysiology-in-traumatic-brain-10i5i3tt5a.pdf

Blood-brain barrier pathophysiology in traumatic brain injury.

Mutations in mitochondrial DNA (mtDNA) associate with various disease states. A few mtDNA mutations strongly associate with diabetes, with the most common mutation being the A3243G mutation in the mitochondrial DNA-encoded tRNA(Leu,UUR) gene. This article describes clinical characteristics of mitochondrial diabetes and its molecular diagnosis. Furthermore, it outlines recent developments in the pathophysiological and molecular mechanisms leading to a diabetic state. A gradual development of pancreatic beta-cell dysfunction upon aging, rather than insulin resistance, is the main mechanism in developing glucose intolerance. Carriers of the A3243G mutation show during a hyperglycemic clamp at 10 mmol/l glucose a marked reduction in first- and second-phase insulin secretion compared with noncarriers. The molecular mechanism by which the A3243G mutation affects insulin secretion may involve an attenuation of cytosolic ADP/ATP levels leading to a resetting of the glucose sensor in the pancreatic beta-cell, such as in maturity-onset diabetes of the young (MODY)-2 patients with mutations in glucokinase. Unlike in MODY2, which is a nonprogressive form of diabetes, mitochondrial diabetes does show a pronounced age-dependent deterioration of pancreatic function indicating involvement of additional processes. Furthermore, one would expect that all mtDNA mutations that affect ATP synthesis lead to diabetes. This is in contrast to clinical observations. The origin of the age-dependent deterioration of pancreatic function in carriers of the A3243G mutation and the contribution of ATP and other mitochondrion-derived factors such as reactive oxygen species to the development of diabetes is discussed.

https://diabetes.diabetesjournals.org/content/diabetes/53/suppl_1/S103.full.pdf

Mitochondrial Diabetes: Molecular Mechanisms and Clinical Presentation

Mitochondria and calcium signaling.

Traumatic brain injury (TBI) is a major health and socioeconomic problem throughout the world. It is a complicated pathological process that consists of primary insults and a secondary insult characterized by a set of biochemical cascades. The imbalance between a higher energy demand for repair of cell damage and decreased energy production led by mitochondrial dysfunction aggravates cell damage. At the cellular level, the main cause of the secondary deleterious cascades is cell damage that is centred in the mitochondria. Excitotoxicity, Ca2+ overload, reactive oxygen species (ROS), Bcl-2 family, caspases and apoptosis inducing factor (AIF) are the main participants in mitochondria-centred cell damage following TBI. Some preclinical and clinical results of mitochondria-targeted therapy show promise. Mitochondria- targeted multipotential therapeutic strategies offer new hope for the successful treatment of TBI and other acute brain injuries.

/pdf/mitochondria-in-traumatic-brain-injury-and-mitochondrial-2vl9r0wb13.pdf

Mitochondria in traumatic brain injury and mitochondrial‐targeted multipotential therapeutic strategies

http://unime.it/__content/files/20131121121003MPTP.pdf

Mitochondrial permeability transition pore is a potential drug target for neurodegeneration

Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria.

The invention concerns a compound comprising at least a cyclosporin molecule and at least a peptide vector capable of transporting said molecule through the blood brain barrier. The invention also concerns the use of said compound for preparing pharmaceutical compositions in particular for treating or preventing disease of the central nervous system.

Compounds, compositions and method for transporting cyclosporin molecules through the blood brain barrier

New cyclosporin compounds (I) comprise at least one cyclosporin molecule (II) and at least one peptide vector (III) capable of transporting (III) across the blood-brain barrier. An Independent claim is included for bonding agents (IV) of formula C(O)-R4-NR1-C(O)-(CH2)n-NH-(CH2)m-C(O)- (IVA), C(O)-R4-NR1-C(O)-R2-NH-R3-C(O)- (IVB), C(O)-R4-NR1-Hyp-O-C(O)-R5-C(O) (IVC), C(O)-R4-NR1-C(O)-CH(NH2)-R5-O-C(O)-R8-C(O) (IVD), C(O)-R4-NR1-C(O)-R5-NH-O-R8-C(O) (IVE), C(O)-R4-NR1-C(O)-R5-O-NH-R8-C(O) (IVF), C(O)-R4-NR1-C(O)-R5-NR7-NR6-R8-C(O) (IVG) or C(O)-R4-NH-R5-C(O) (IVH). m, n = at least 1; R1 = H, OR6, NR6R7, alkyl, aryl, alkaryl, acyl or allyl; R2, R3 = alkyl, at least one of which is branched by one or two or a combination of alkyl, aryl, alkaryl, acyl or allyl or any other type of branched alkyl (optionally containing heteroatom groups); R4-R6 = linear alkyl or branched alkyl as defined for R2/R3; R1 = H, alkyl, aryl, alkaryl, acyl or allyl, and Hyp-O = hydroxyproline residue, in which the OH group is in the 2, 3 or 4-position of the proline and bonding is via the O of the OH group of the hydroxyproline. Asymmetric carbons have R- or S-configuration.

New cyclosporin derivatives, containing bonded peptide vector for crossing blood-brain barrier, used for treating cerebral disorders such as neurodegenerative diseases, cerebral trauma or cerebrovascular accidents

La presente invention concerne un compose qui comprend au moins une molecule de cyclosporine et au moins un vecteur peptidique capable de transporter ladite molecule a travers la barriere hemato-encephalique. L'invention concerne aussi l'utilisation dudit compose pour la preparation de compositions pharmaceutiques destinees notamment au traitement ou a la prevention de maladie du systeme nerveux central.

Composes, compositions et methode pour le transport des molecules de cyclosporine a travers la barriere hemato-encephalique

The invention relates to a compound comprising at least one active substance and at least one carrier, said active substance and carrier being connected by at least one binding agent The invention also relates to the use of the compound for the preparation of a pharmaceutical composition and to said pharmaceutical composition The invention further relates to the aforementioned binding agents

Compounds comprising at least one active substance and at least one carrier which are connected by a binding agent, uses thereof and said binding agents

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