Central Nervous System Agents in Medicinal Chemistry - Volume 7, Issue 2, 2007

Neurogenesis continues throughout adulthood in the central nervous system in mammals. Cerebral ischemia induces neurogenesis in the subventricular zone and dentate gyrus. New neurons migrate to the granule cell layer of dentate gyrus or to the damaged CA1 region and striatum, where they differentiate into mature neurons and re-establish connections. Ischemic insults also promote axonal sprouting in ischemic penumbra. Neurogenesis and axonal sprouting may contribute to functional recovery after cerebral ischemia.

Nitric oxide (NO) and carbomonoxide (CO) are gaseous molecules that have been recently implicated in a series of activities in the nervous system. These cellular messengers function as neurotransmitters, and their neurodegenerative and neuroprotective actions observed in in vitro and in vivo suggest participation of these gases in cell survival and neuronal differentiation. Lack of NO resulted in cell death in neuronal cell lines and is accompanied by neuropathological conditions in animal models. Altered adult neurogenesis was found in NO-synthetase knock-out animals. Moreover, animals with NO-shortage showed defects in hippocampal long term potentiation and retinal map formation. Abnormalities in CO- metabolism and -function are involved in neurodegenerative disease states. This review summarizes the historical record of evidences for NO and CO functions in the nervous system, and describes the participation of these second messengers in the early steps of neuronal differentiation during embryonic development, i.e. migration, dendritic and axonal growth, and synaptogenesis. Moreover, the localization of NO- and CO- synthesis and the intracellular targets of these gases and their downstream targets, such as cGMP and their respective receptors, are discussed. The association of expression of NO- and CO- induced signaling cascades with glutamate receptors activating NO- and CO- production, provides strong evidence regarding the participation of these gases in formation of the nervous system. These mechanisms indicate novel targets for therapeutic intervention in disease states resulting from the lack of NO- and CO-synthesis.

There are numerous evidences about the effects of crude snake venoms or isolated toxins on the peripheral nervous system. However, the data on their interactions with the central nervous system (CNS) are not so abundant, since the blood-brain barrier (BBB) impedes penetration of these compounds into the brain. There are several reviews describing the interactions of particular classes of snake venom polypeptides with components of the CNS; however, no general systematics of such interactions was done. This review is the first attempt to consolidate the data about the interaction of snake venom polypeptides with the CNS. Such data will be described according to three main modes of interactions: - Direct in vivo interaction of the CNS with venom polypeptides capable to penetrate BBB. - In vitro interactions of isolated components of the CNS with crude venoms or purified toxins. - Indirect effects of snake venoms or their components on functioning of the CNS under normal or pathological conditions. Although the venom components penetrating BBB are not numerous, they seem to be the most suitable candidates for the leads in drug design. The compounds from two other groups are more abundant and better studied, but the fact that the data about their ability to penetrate BBB are still absent may substantially aggravate the potentials for their medical perspectives. Nevertheless, many of these compounds are used as biochemical tools for research of the CNS in vitro. These investigations may give invaluable information for understanding the molecular basis of CNS diseases and thus lay the basis for targeted drug design. This aspect also will be outlined in the review.

Senescence is an ageing process characterized by progressive and irreversible dysfunction of various physiological systems. Physiological senescence with advancing age is not a disease, but it affects the life-span and life-quality of elderly people. Brain functions such as cognition and motor skills, as with other organ systems, are impaired in almost all elderly people. Neuroprotective dietary components can play a key role in ensuring healthy ageing of the brain. Although the causative mechanisms of senescence are complex and not yet fully elucidated, enhanced oxidative stress is thought to be an important contributor. Dietary antioxidants from fruits and vegetables have preventative effects on oxidative stress. Catechin, a polyphenol found in green tea, has a potent antioxidative effect. Recently, catechin has been reported to protect against reduced ageing-related cognitive functions such as those associated with learning and memory, and ischemic brain damage. Catechin may act as a neuroprotective agent in progressive neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The neuroprotective effects and putative mechanisms of action of catechin and other antioxidants are examined and discussed in this review.

During neurogenesis, precursor cells undergo a defined number of divisions and terminally differentiate as postmitotic neurons. In the adult mammal, under certain conditions, postmitotic neurons re-enter the cell cycle and divide. The accumulated evidence demonstrates that the precise control of cell-cycle progression is critical for both neuronal development and maintenance of the neuronal phenotype. Cyclin-dependent Kinase Inhibitors (CDKIs) play the key role in this neuronal differentiation process of coordinating cell cycle exit and differentiation. Importantly, deregulation of the cell cycle leads to a variety of human neuronal diseases. In this review we discuss how regulation of neuronal progenitor proliferation and neuronal differentiation are coupled processes, based on evidence derived from the study of multiple animal models (mouse, Drosophila and Xenopus). In addition, we discuss the involvement of CDKIs in human neuronal diseases including cancers of neuronal systems, Alzheimer’s disease, and psychological disorders, and their potential as pharmacological targets.

The discovery of metabotropic gamma-aminobutyric acid(B) (GABAB) receptors has enormously influenced our understanding of GABAergic neurotransmission in the central nervous system. These G-protein coupled receptors play critical roles in neuronal and glial functions, such as neuronal excitability and modulation of synaptic neurotransmission. Moreover they are involved in a variety of neurodegenerative and pathophysiological disorders, including epilepsy, spasticity, chronic pain, depression, schizophrenia, and drug addiction. GABAB receptor function is regulated by differences in expression and interactions with effector ion channels, mainly by inwardly rectifying K+ channels and voltagegated Ca2+ channels, and other signaling proteins on the neuronal surface. These receptors are widely expressed and distributed in the nervous system, being localized to both pre- and postsynaptic sites. Although GABAB receptors can be targeted to GABAergic synapses, they are mostly associated with glutamatergic synapses. Therefore, it is expected that this wide and heterogeneous distribution of GABAB receptors will open new opportunities for the development of pharmacological tools and new therapeutic strategies. Over the past decade, a number of agonists, antagonists and allosteric modulators selective for GABAB receptors have been developed. The combination of these pharmacological tools with genetic approaches is helping to elucidate the roles of GABAB receptors in the regulation of nervous system function in normal and pathological conditions. Moreover, these studies suggest that drugs active at GABAB receptors are interesting new targets to treat a wide variety of neurological and psychiatric disorders.

T11TS/SLFA-3, the glycoprotein isolated from sheep erythrocyte membrane, acts as an antineoplastic agent causing apoptotic elimination of glioma cells through cell mediated immune response. Therefore, elucidation of the proper balance in proliferation and apoptosis of neuroimmune components viz. microglia and brain infiltrating lymphocytes with the neoplastic glial cells was the fundamental issue to establish the efficacy of T11TS as a therapeutic agent in glioma. To decipher its effectivity on proliferation rate of glioma cells, expression of GFAP and cell cycle phase distribution was analyzed with propidium iodide (PI) staining. The apoptotic regulation of interacting immuno-competent microglia, lymphocytes entering into the brain and target glioma cells were elucidated by cytoplasmic DNA fragmentation assay and phosphatidylserine (PS) externalization along with intrinsic p53 and Bcl-2 modulation of the cells. With the reduction of cellular proliferation rate, sharp increase of apoptosis in consecutive doses of T11TS showed the regression of glioma, where an increase of cytosolic p53 and a decrease of Bcl-2 with doses in these neoplastic cells facilitate the process. Resident microglia, the chief immunomodulator of brain, was found to show a low and steady level of proliferation and apoptosis, furnishing it as a stable pool of cells capable of controlling immune reaction in brain compartment. However, microglia showed higher basal level of p53 compared to the other cells in study and being modulated with T11TS dose, it was found to possess a steady level of Bcl-2 that aided to maintain low rate of apoptosis. Brain infiltrating lymphocytes showed increased apoptosis in tumorigenic condition and initial treatment phase mostly due to immuno-suppressive milieu and deprivation of microglial restimulation. But the second dose of T11TS showed reduced apoptosis, enhanced activation of lymphocytes and final dose acting as a regulatory dose, which reduce the infiltrating lymphocytes by apoptotic elimination. Wide fluctuation of cytosolic p53 was observed in these lymphocytes, but anti-apoptotic Bcl-2 was found to modulate apoptosis in the cells. Thus, T11TS was found to differentially regulate the population of immune effector cells against glioma to exert effective effector function in eradication of neoplastic cells where Bcl-2 constitutively suppresses pro-apoptotic function of p53. Regulation of the direction of these balances of cellular life and death in favor of glioma killing and also maintaining homeostasis in brain tissue after reaction established T11TS as an effective therapeutic probe against glioma.