Animal Models Of Head Injury Research Articles

Science, Anaesthesia and animal studies: what is ‘evidence’?

Science, <i>Anaesthesia</i> and animal studies: what is ‘evidence’?

Apoptosis: A Target for Neuroprotection

Accumulating evidence strongly suggests that apoptosis contributes to neuronal death in a variety of neuro-degenerative contexts. Activation of the cysteine protease caspase 3 appears to be a key event in the execution of apoptosis in the central nervous system. As a result, mice null for caspase 3 display considerable neuronal expansion, usually resulting in death by the second week of life. Consistent with the proposal that apoptosis plays a central role in human neurodegenerative disease, caspase-3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzheimer’s disease. Indeed, peptide-based caspase inhibitors prevent neuronal loss in animal models of head injury and stroke, suggesting that these compounds may be the forerunners of non-peptide small molecules that halt the apoptotic process implicated in these neurodegenerative disorders. The present review will summarise some of the recent data suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditions.

Bone morphogenetic proteins and bone morphogenetic protein gene therapy in neurological surgery: a review.

To review the uses of bone morphogenetic proteins (BMPs) and BMP gene therapy for the treatment of neurosurgical disorders. Literature review. BMPs are members of the transforming growth factor beta superfamily, and they play an important role in the growth and development of numerous tissues, including bone, brain, and spinal cord. Although the majority of previous studies have focused on the regulatory functions of BMPs in the normal growth and differentiation of the skeletal system, BMPs also seem to be exquisitely involved in the regulation of cellular proliferation, survival, differentiation, apoptosis, and lineage commitment in the central nervous system. When specific BMPs are delivered on biological matrices, they have the capacity to induce bone, cartilage, ligament, and tendon at both heterotopic and orthotopic sites, suggesting that they may play a major role in the future treatment of spinal and craniofacial pathology. For example, recent studies have clearly demonstrated the usefulness of BMPs and BMP gene therapy for the induction of spinal arthrodesis in several animal models. In addition, several BMPs have been shown to have a neuroprotective effect in animal models of head injury, cerebral ischemia, and Parkinson's disease and may therefore have direct clinical applications for the treatment of central nervous system disorders. As the physiological activity of BMPs in the development and pathology of the central nervous system and spine are more fully elucidated, BMP therapeutics and gene therapy will probably have numerous applications in neurological surgery.

Neuroprotection by the inhibition of apoptosis.

Accumulating evidence strongly suggests that apoptosis contributes to neuronal cell death in a variety of neurodegenerative contexts. Activation of the cysteine protease caspase-3 appears to be a key event in the execution of apoptosis in the central nervous system (CNS). As a result, mice null for caspase-3 display considerable neuronal expansion usually resulting in death by the second week of life. At present, 14 caspase family members have been identified and subdivided into three subgroups on the basis of preference for specific tetrapeptide motifs using a positional scanning combinatorial substrate library. Caspase-3 is a group II member (2, 3, 7) categorized by an absolute substrate requirement for aspartic acid in the P4 position of the scissile bond. The preferred cleavage motif (DExD) for group II caspases is found in many structural, metabolic and repair proteins essential for cellular homeostasis. Consistent with the proposal that apoptosis plays a central in role human neurodegenerative disease, caspase-3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzheimer's disease. Indeed, peptide-based caspase inhibitors prevent neuronal loss in animal models of head injury and stroke suggesting that these compounds may be the forerunners of non-peptide small molecules that halt apoptosis processes implicated in these neurodegenerative disorders. A clear link between an hereditary neurodegenerative disorder and failed caspase inhibition has recently been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal specific inhibitor of apoptosis (IAP) family member known as NAIP is often dysfunctional due to missense and truncation mutations. IAPs such as NAIP potently block the enzymatic activity of group II caspases (3 and 7) suggesting that NAIP mutations may permit unopposed developmental apoptosis to occur in sensory and motor systems resulting in lethal muscular atrophy. Conversely, adenovirally-mediated overexpression of NAIP or the X-linked IAP called XIAP reduces the loss of CA1 hippocampal neurons following transient forebrain ischemia. Taken together, these findings suggest that anti-apoptotic strategies may some day have utility in the treatment of neurodegenerative disease. The present review will summarize some of the recent evidence suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditions.

Patent Analysis Central &amp; Peripheral Nervous Systems: NMDA receptor antagonists: Patent analysis 1990–1995

The publication twelve years ago of evidence supporting the use of N-methyl-D-aspartate (NMDA) receptor antagonists as neuroprotectives in animal models of head injury has provoked a great deal of interest in the use of NMDA receptor antagonists in humans to prevent the significant secondary insults caused by head trauma (such as cellular hypoxia and brain swelling) which occur in the post-injury period, i.e., to act as neuroprotectives. This article analyses the trends in research, identifying the key compounds in development with a focus on future drugs.

HYPERTONIC SALINE (7.5%) VERSUS MANNITOL

Hypertonic saline (7.5% NaCl = HS) was compared with 20% mannitol (MAN), for the treatment of increased intracranial pressure (ICP), in a large animal model of head injury. Sheep were instrumented for hemodynamic and ICP monitoring and fluid administration. Elevated ICP (20-25 mm Hg) was produced by inflating an epidural balloon for 1 hour. Animals were then given a bolus of 250 mL of either HS (n = 7) or MAN (n = 7) and monitored for 2 hours. No significant differences in hemodynamic variables were noted between groups. The ICP decreased to the same degree in both groups during the 2 hours of observation (HS = 11 +/- 3.8 mm Hg; MAN = 8 +/- 2 mm Hg). Brain water contents were also similar (HS = 3.68 +/- 0.09 mL H2O/g dry wt; MAN = 3.83 +/- 0.08 mL H2O/g dry wt). The 7.5% NaCl was equally effective in treating elevated ICP caused by a space-occupying lesion when compared with 20% mannitol. Hypertonic saline has the additional benefit of rapid cardiovascular resuscitation of associated hemorrhagic shock with small-volume infusion.