LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro.

Neurotrophic factors are known to play a crucial role in the elongation and guidance of auditory nerve fibres to their targets within the organ of Corti. Maintenance of these neural connections following deafness would clearly influence the efficacy of therapies for hearing recovery. The growth factors leukaemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta 5 (TGF-beta5) were tested for their efficacy in promoting neurite outgrowth from dissociated cultures of early postnatal rat auditory neurons. Our results indicate that while BDNF enhances neurite outgrowth in a strong fashion, LIF is more potent; moreover, the combined administration of both factors has even greater neuritogenic capacities. TGF-beta5, although neurotrophic, has no neuritogenic activity on cultured auditory neurons. LIF and BDNF may therefore be potential candidates when developing pharmacological therapies for hearing recovery.

The neurotrophins act synergistically with LIF and members of the TGF-beta superfamily to promote the survival of spiral ganglia neurons in vitro.

A number of growth factor families have been implicated in normal inner ear development, auditory neuron survival and protection. Several growth factors, including transforming growth factor-beta5 (TGF-beta5) and TGF-beta3, neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) were tested for their ability, individually or in combination, to promote auditory neuron survival in dissociated cell cultures of early rat post-natal spiral ganglion cells (SGCs). The results indicate that at discrete concentrations all growth factors act in an additive fashion and some in synergy when promoting neuronal survival. These findings support the hypothesis that growth factors from different families may be interdependent when sustaining neuronal integrity.

Growth factors, auditory neurones and cochlear implants: a review.

The total number and the integrity of the auditory neurones available for stimulation govern the benefits that patients can derive from cochlear implants. Although electrical stimulation of the cochlea has been reported to promote auditory neuronal survival, this trophic effect is insufficient to regenerate de novo fibres. Hence, any agent that can maximize the number of, or regenerate functional auditory neurones would be of great benefit. Several studies have identified various growth factors crucial to the normal development of auditory neurones. In addition, in vitro studies have demonstrated that several growth factors are important for the maintenance, rescue and repair of adult auditory neurones. In vivo studies confirm the in vitro findings, reporting that specific growth factors are able to support auditory neuronal survival following injury or trauma, and in lower species growth factors have been associated with regenerating auditory neurones. In addition to their trophic actions, several growth factors have also been reported to affect ion channels thus the electrical response of neuronal fibres. Indeed, growth factors have been reported to enhance neuronal excitation and to improve the efficacy of synaptic transmission. Taken in concert, these effects suggest that exogenous growth factors delivered to the cochlea may improve the transmission of the electrical stimuli from the implanted electrode to the auditory pathway. Further studies are warranted to investigate how the adjunct delivery of growth factors with the cochlear implant may constitute a better treatment for hearing-impaired individuals.

Synergy between TGF-beta 3 and NT-3 to promote the survival of spiral ganglia neurones in vitro.

Transforming growth factor-betas (TGF-betas) have been implicated in normal inner ear development and in promoting neuronal survival. Early rat post-natal spiral ganglion cells (SGC) in dissociated cell culture were used as a model of auditory innervation to test the trophic factors TGF-beta3 and neurotrophin-3 (NT-3) for their ability, individually or in combination, to promote neuronal survival. The findings from this study suggest that TGF-beta3 supports neuronal survival in a concentration-dependent manner. Moreover TGF-beta3 and NT-3-potentiated spiral ganglion neuronal survival in a synergistic fashion.

The binding of both [3H]nemonapride and [3H]raclopride is increased in schizophrenia.

We performed a postmortem autoradiographic study to compare the density of dopamine D4-like sites in caudate putamen section from age-matched schizophrenia (n = 15) and control (n = 15) populations. The densities of the D4-like sites were estimated by subtracting the density of [3H]raclopride (binding D2 and D3 receptors) from the density of [3H]nemonapride (binding D2, D3, and D4 receptors). The findings revealed that in the schizophrenia population there was a significant increase in the binding of both [3H]nemonapride (2.3-fold) and [3H]raclopride (1.9-fold). In addition, in the schizophrenia population the density of D4-like sites was increased 2.6-fold.

LIF potentiates the NT-3-mediated survival of spiral ganglia neurones in vitro.

The survival of auditory neurones depends on the continued supply of trophic factors. Early postnatal spiral ganglion cells (SGC) in a dissociated cell culture were used as a model of auditory innervation to test the trophic factors leukaemia inhibitory factor (LIF) and neurotrophin-3 (NT-3) for their ability, individually or in combination, to promote neuronal survival. The findings suggest that LIF supports neuronal survival in a concentration-dependent manner. Moreover LIF potentiated NT-3-mediated spiral ganglion neuronal survival in a synergistic fashion.

[3H]nemonapride binding in human caudate and putamen.

The binding of [3H]nemonapride to human postmortem caudate and putamen tissue was autoradiographically investigated using several antipsychotic drugs. Saturation experiments revealed a single population of binding sites (dissociation constant (KD) 0.38 +/- 0.01 nM, and total binding capacity (BMAX) 55 fmol/TE). Prototypic dopamine (DA) receptors antagonists displaced [3H]nemonapride in a monophasic manner. The order of displacement potency was expected for DA D2-like receptors: spiperone > (+)butaclamol > or = chlorpromazine > (-)sulpiride > ketanserin. Displacement with serotonergic antagonists suggests that in human caudate and putamen tissue [3H]nemonapride may have a very low affinity serotonergic component. However, [3H]nemonapride displays a high affinity and selectivity for DA D2-like receptors and should make, it a preferred compound for tritium-based autoradiography.