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ABSTRACTThirty children aged 3-10 years with clinically confirmed or suspected Duchenne Muscular Dystrophy (DMD) were analyzed for chromosomal aberrations using cytological preparations, biochemical changes using enzyme kit protocol, and deletions in the 26 exons of the DMDgene by targeting the mutations at the proximal and distal ‘hot spot’ regions of the dystrophin gene in South Indian patients with DMD. The frequenc y of chromosomal aberrations (both chromosomal and chromatid-type) and serum enzyme levels were significa ntly elevated in DMD subjects as compared to controls. Multiplex PCR assays revealed 27 patients having deletions in the DMDgene located at the distal ‘hot spot’ region. This study suggests that disease progression is directly associated with higher incidence of the deletions at the distal ‘hot spot’ of the DMDgene.

Mitochondrial dysfunction plausibly underlies the aging-associated brain degeneration. Mitochondria play a pivotal role in cellular bioenergetics and cell-survival. Oxidative stress consequent to chronic hypoperfusion induces mitochondrial damage, which is implicated as the primary cause of cerebrovascular accidents (CVA) mediated Alzheimers disease (AD). The mitochondrial function deteriorates with aging, and the mitochondrial damage correlates with increased intracellular production of oxidants and pro-oxidants. The prolonged oxidative stress and the resultant hypoperfusion in the brain tissues stimulate the expression of nitric oxide synthase (NOS) enzymes, which further drives the formation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The ROS and RNS collectively contributes to the dysfunction of the blood-brain barrier (BBB) and damage to the brain parenchymal cells. Delineating the molecular mechanisms of these processes may provide clues for the novel therapeutic targets for CVA and AD patients.

Treatment with neurotrophic agents might enhance and/or prolong the effects of cholinesterase inhibitors (ChEIs) in Alzheimers disease (AD). We compared the safety and efficacy of the neurotrophic compound Cerebrolysin (10 ml; n64), donepezil (10 mg; n66) and a combination of both treatments (n67) in mild-to-moderate (mini-mental state examination-MMSE score 12-25) probable AD patients enrolled in a randomized, double-blind trial. Primary endpoints were global outcome (Clinicians Interview-Based Impression of Change plus caregiver input; CIBIC) and cognition (change from baseline in AD Assessment Scale-cognitive subscale; ADAS-cog) at week 28. Changes in functioning (AD Cooperative Study-Activities of Daily Living scale, ADCS-ADL) and behaviour (Neuropsychiatric Inventory, NPI) were secondary endpoints. Treatment effects in cognitive, functional and behavioral domains showed no significant group differences; whereas improvements in global outcome favored Cerebrolysin and the combination therapy. Cognitive performance improved in all treatment groups (mean±SD for Cerebrolysin: -1.7±7.5; donepezil: -1.2±6.1; combination: - 2.3±6.0) with best scores in the combined therapy group at all study visits. Cerebrolysin was as effective as donepezil, and the combination of neurotrophic (Cerebrolysin) and cholinergic (donepezil) treatment was safe in mild-to-moderate AD. The convenience of exploring long-term synergistic effects of this combined therapy is suggested.

The influence of brain histamine (HA) on learning and memory is not well understood, although some reports indicate that HA improves memory consolidation. We have studied the effects of α-fluoromethylhistidine (FMH) (100 mg/Kg, i.p.), which reduced by 60–80% the concentration of hypothalamic HA, on rat locomotor activity (LA) and learning in several experimental conditions in a computerized system. FMH reduced LA in an open field paradigm (OFP) 3h after injection and tended to inhibit motor habituation after a 3-day trial. In a maze paradigm (MP), where the animals had to learn to avoid a foot-shock (1 mA), FMH reduced LA, rearing (2F), and jumping activity (JA). The peripheral administration of HA to control-trained rats reduced a learning index (N/Sts ratio) by 50%. According to these results, FMH diminished LA, 2F, and JA with no effect on habituation in MP. These observations might indicate that a moderate reduction in the levels of brain HA might enhance attention in solving visuo-spatial tasks under stressful stimuli.

Histamine (HA) is a biogenic amine involved in the regulation of neurovegetative, cognitive, neuroendocrine and neuroimmune functions in the central nervous system (CNS). A bidirectional interaction between the CNS and the neuroimmune system has been demonstrated in recent years. However, data concerning brain HA-cytokine interactions are scarce. In this study we have evaluated tumor necrosis factor-alpha (TNF-α) levels in the posterior hypothalamic region (PHR) and hipocampus (HP) of rats with: (a) bilateral ibotenic acid neurotoxic lesions in histaminergic neurons located in the PHR (I); (b) saline injections in the PHR (S); and (c) sham operation (C), two weeks after neurosurgery. The bilateral disruption of PHR HA neurons with ibotenic acid decreased TNF-α levels in the PHR with respect to shamoperated (C), but not saline-injected (S), rats. In contrast, hippocampal TNF-α concentrations were higher in lesioned rats (I) than inC andS animals. Our results indicate that the neurotoxic destruction of HA neurons decreases TNF-α synthesis in the hypothalamus while enhancing TNF-α production in the hippocampus, suggesting that neuronal HA might be involved in the regulation of the brain TNF-α system.

Brain histaminergic and cholinergic systems are involved in the neuromodulation of cognitive functions and altered in some neuropsychiatric disorders such as Alzheimer's disease. In this study we have investigated the effects of betahistine dihydrochloride (BH) on locomotor activity (LA) and passive avoidance behavior (PAB) in control and scopolamine(SC)-treated male rats. In an open-field paradigm, BH increased LA at high doses and inhibited SC-induced hyperactivity at moderate ones, without effect on motor habituation. In an electronic maze paradigm, in which animals had to learn to avoid a 1.5 mA electric shock, BH reduced the number of trials required by SC-treated animals to learn to stay in a neutral platform during two consecutive trials. These results seem to indicate that BH influences basal and SC-induced locomotor activity, and attenuates the learning impairment caused by SC.

Besides the role of histamine (HA) as a neurotransmitter, a new concept has emerged presenting HA as an immunomodulator. Several studies have demonstrated interactions among HA, interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF), suggesting a possible bidirectional communication among them. In this study we have investigated the effects of i.p. administrations of HA diphosphate (6 µmol/kg) anda-fluoromethylhistidine (FMH; 100 mg/kg) on TNF-a levels in the hippocampus, hypothalamus, and posterior hypothalamic region of the rat brain. The concentrations of TNF-a at 0 (Control, C) and 30 min after i.p. administration of HA were 0.26 ± 0.02 pg/mg and 0.32 ± 0.02 pg/mg in the hippocampus, 0.46 ± 0.04 pg/mg and 0.09 ± 0.006 pg/mg (p < 0.01) in the hypothalamus, and 0.47 ± 0.05 pg/mg and 0.26 ± 0.05 pg/mg in the posterior hypothalamic region. Three hours after FMH administration, an increase in the hippocampal levels of TNF-a was observed (0.43 ± 0.04 pg/mg; p < 0.01), while in the hypothalamus (0.11 ± 0.02 pg/mg; p < 0.01) and in the posterior hypothalamic region (0.21 ± 0.04 pg/mg; p < 0.05) a decrease in TNF-a levels was detected. These results suggest that changes in the histaminergic system influence TNF-a production in the brain in an area-specific fashion.

Histamine (HA) acts as a neurotransmitter and/or neuromodulator in mammalian brain. Central HA has been found to be involved in the regulation of behavioral, cognitive, neurovegetative, neuroendocrine and neuroimmune functions. In this study we have evaluated psychomotor activity (PMA) and passive avoidance behavior (PAB) in rats with bilateral neurotoxic lesions in the posterior hypothalamic region (PHR) (L), where histaminergic neurons are located, and in sham-operated rats (S), two weeks after neurosurgery. In an open-field paradigm, lesioned rats showed higher PMA scores than sham-operated animals. However, L rats exhibited a significant decrease in PMA on consecutive days (motor habituation) similar to that found in S rats. In a maze paradigm, in which the animals had to learn to stay on a neutral platform in order to avoid a 1.5 mA electric footshock during 10 trails, no significant differences were observed between L and S rats on the task performance. According to the present results, it seems that bilateral neurotoxic lesions in the PHR induced hyperactivity with no apparent effects on PAB, suggesting that neuronal HA might be involved, directly and/or by influencing arousal/alertness-mediated mechanisms, in the regulation of PMA processes.

Some recent studies give support to the potential interaction between histamine (HA) and interleukin-1 (IL-1) in the central nervous system (CNS). At the peripheral level, HA acts as an immune modulator, but little is known on the neuroimmune role of this biogenic amine in the CNS. In the present study we have investigated the effects of HA, mepyramine, famotidine, thioperamide, and L-histidine on hypothalamic IL-1β. HA induced a time- and dose-dependent decrease in the concentration of IL-1β. The maximum effect was obtained 30 minutes after injection. The HA-induced IL-1β response in the hypothalamus was not inhibited by either mepyramine, famotidine or thioperamide. In addition, L-histidine exerted the same effect as HA. The interaction between HA and IL-1β in the CNS might be linked to neuroendocrine regulation as well as to neurotrophic activity and neuroimmune function.

The immune system is subject to destruction and dysfunction as a result of attacks by pathogenic and environmental agents. In addition, many clinical situations exist in which it is desirable to stimulate or suppress the immune system. The present study evaluated the screening efficacy of flow cytometric lymphocyte subset typing in peripheral blood mononuclear cells from healthy individuals (HI) and from patients with non-Hodgkin lymphoma (NHL) treated with different concentrations of FR-91, a standardized lysate of microbial cells belonging to the Bacillus genus, and in vitro cytokine production. Increased expression of subset markers (CD3, CD4, CD8) in NHL and CD3 in HI suggests an immunomodulating effect of FR-91. In addition the results of cytokine production also demonstrated a clear effect of FR-91 on both populations. A significant increase of IL-6, IL-12, IFN-γ and TNF-α was observed in the HI group after treatment with FR-91. In a similar manner an increase of IL-2, IL-6, IL-12, IFN-γ and TNF-α was also observed in the NHL group. In conclusion FR-91 seems to affect lymphocyte subpopulations, in vitro cytokine production, as well as mitogen-induced lymphocyte activation in a dose-dependent manner in both healthy individuals and NHL patients.