Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed.

There is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. Using transgenic mice that overexpress aldose reductase (AR) in their lenses, we found that the flux of glucose through the polyol pathway is the major cause of hyperglycemic oxidative stress in this tissue. The substantial decrease in the level of reduced glutathione (GSH) with concomitant rise in the level of lipid peroxidation product malondialdehyde (MDA) in the lens of transgenic mice, but not in the nontransgenic mice, suggests that glucose autoxidation and nonenzymatic glycation do not contribute significantly to oxidative stress in diabetic lenses. AR reduction of glucose to sorbitol probably contributes to oxidative stress by depleting its cofactor NADPH, which is also required for the regeneration of GSH. Sorbitol dehydrogenase, the second enzyme in the polyol pathway that converts sorbitol to fructose, also contributes to oxidative stress, most likely because depletion of its cofactor NAD+ leads to more glucose being channeled through the polyol pathway. Despite a more than 100% increase of MDA, oxidative stress plays only a minor role in the development of cataract in this acute diabetic cataract model. However, chronic oxidative stress generated by the polyol pathway is likely to be an important contributing factor in the slow-developing diabetic cataract as well as in the development of other diabetic complications.--Lee, A. Y. W., Chung, S. S. M. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13, 23-30 (1999)

Aldose reductase (AR) has been implicated in the etiology of diabetic cataract, as well as in other complications. However, the role of AR in these complications remains controversial because the strongest supporting evidence is drawn from the use of AR inhibitors for which specificity in vivo cannot be ascertained. To settle this issue we developed transgenic mice that overexpress AR in their lens epithelial cells and found that they become susceptible to the development of diabetic and galactose cataracts. When the sorbitol dehydrogenase-deficient mutation is also present in these transgenic mice, greater accumulation of sorbitol and further acceleration of diabetic cataract develop. These genetic studies demonstrated convincingly that accumulation of polyols from the reduction of hexose by AR leads to the formation of sugar cataracts.Diabetic complications such as neuropathy, nephropathy, retinopathy, and cataract, etc., occur in both insulin-dependent and noninsulin-dependent diabetes mellitus. Hyperglycemia has long been suspected as the cause of these manifestations, and the results of the Diabetic Control and Complications Trial (1) appear to confirm it. However, by what mechanism elevated blood glucose leads to these complications is unclear. One theory implicates the polyol pathway as a cause of diabetic cataract because of the discovery of polyols in cataractous lenses (2) and the identification of aldose reductase (AR) that reduces various sugars to their polyols (3, 4). AR reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase (SorD). Because sorbitol does not readily diffuse out of cells and its oxidation to fructose is slow, the accumulation of sorbitol under the hyperglycemic state would increase the intracellular osmotic pressure, leading to swelling and eventual rupture of the lens fiber cells (5). The involvement of AR in diabetic cataract is supported by the fact that animals such as rats and dogs that have high levels of this enzyme in their lenses are prone to develop diabetic cataract, whereas mice that have low lens AR activity are not (6). Rats and dogs also develop galactose-induced cataracts more readily than diabetes-induced cataracts (7). This fact agrees with the polyol model because galactose is a better substrate than glucose for AR in vitro, and its reduction product galactitol is not further converted to other metabolites, resulting in faster buildup of this polyol. Additional evidence for the polyol model came from the fact that several AR inhibitors could suppress cataract formation in experimentally induced diabetic animals (8-10). However, these drugs may inhibit AR by nonspecific hydrophobic interactions (11,12), and their beneficial effects may be derived from the inhibition of other enzymes. The strongest challenge to the polyol model is the fact that kinetic analyses (13, 14) and x-ray crystallographic studies (15) indicated that AR has a very low affinity for glucose and galactose, and it has not been demonstrated directly that...

NCAM, a neural cell adhesion molecule of the immunoglobulin superfamily, is involved in neuronal migration and differentiation, axon outgrowth and fasciculation, and synaptic plasticity. To dissociate the functional roles of NCAM in the adult brain from developmental abnormalities, we generated a mutant in which the NCAM gene is inactivated by cre-recombinase under the control of the calciumcalmodulin-dependent kinase II promoter, resulting in reduction of NCAM expression predominantly in the hippocampus. This mutant (NCAMffϩ) did not show the overt morphological and behavioral abnormalities previously observed in constitutive NCAM-deficient (NCAMϪ/Ϫ) mice. However, similar to the NCAMϪ/Ϫ mouse, a reduction in long-term potentiation (LTP) in the CA1 region of the hippocampus was revealed. Long-term depression was also abolished in NCAMffϩ mice. The deficit in LTP could be rescued by elevation of extracellular Ca 2ϩ concentrations from 1.5 or 2.0 to 2.5 mM, suggesting an involvement of NCAM in regulation of Ca 2ϩ -dependent signaling during LTP. Contrary to the NCAMϪ/Ϫ mouse, LTP in the CA3 region was normal, consistent with normal mossy fiber lamination in NCAMffϩ as opposed to abnormal lamination in NCAMϪ/Ϫ mice. NCAMffϩ mutants did not show general deficits in short-and long-term memory in global landmark navigation in the water maze but were delayed in the acquisition of precise spatial orientation, a deficit that could be overcome by training. Thus, mice conditionally deficient in hippocampal NCAM expression in the adult share certain abnormalities characteristic of NCAMϪ/Ϫ mice, highlighting the role of NCAM in the regulation of synaptic plasticity in the CA1 region.