PMID- 26433686
OWN - NLM
STAT- MEDLINE
DCOM- 20161017
LR  - 20161230
IS  - 1532-2777 (Electronic)
IS  - 0306-9877 (Linking)
VI  - 85
IP  - 6
DP  - 2015 Dec
TI  - Early disruption of neurovascular units and microcirculatory dysfunction in the 
      spinal cord in spinal muscular atrophy type I.
PG  - 842-5
LID - S0306-9877(15)00371-0 [pii]
LID - 10.1016/j.mehy.2015.09.028 [doi]
AB  - Spinal muscular atrophy type I (SMA-I) is characterized by progressive muscle 
      weakness with onset in early infancy, usually resulting in mortality before two 
      years of age. However, the processes underlying the pathophysiological 
      progression of the disease remain unclear. Prior to the onset of muscle weakness, 
      a regression of local capillaries is observed along with motor neuron loss. Local 
      populations of neurons, astrocytes, and vascular endothelial cells constitute a 
      neurovascular unit (NVU), in which neuronal and synaptic metabolism is tightly 
      coupled to capillary blood flow by astrocyte-mediated vasodilatory control. We 
      hypothesize that survival motor neuron protein deficiency and initial neuronal 
      dysfunction leads to the regression of vascular beds and the disruption of NVU 
      function. As a result, local capillary blood flow becomes insufficient, leading 
      to metabolic stress in neurons, endothelial cells, pericytes, and astrocytes, 
      ultimately disrupting the astrocytic regulation of capillaries. This pathogenic 
      process may accelerate the loss of anterior horn motor neurons, leading to the 
      further regression of capillaries and astroglial dysfunction. Hypocapnia, 
      resulting from dehydration and hyperventilation during therapeutic manual 
      ventilation, might further damage the NVU. Moreover, disruption of the 
      microcirculation may affect sympathetic and sensory neurons in the spinal cord, 
      contributing to sympathetic hyperactivity and sensory nerve degeneration, 
      respectively. These mutually reinforcing processes may underlie the progression 
      of muscle weakness during infancy in SMA-I. Therefore, disruption of the NVU and 
      a stressful neurovascular environment in the anterior horn may play important 
      roles in disease initiation and/or progression in SMA-I. The NVU is therefore a 
      critical therapeutic target for treating SMA-I. Our hypothetical model may 
      provide insight into why most neuroprotective strategies that do not address 
      astroglial and vascular cell dysfunction have limited efficacy.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Nobutoki, Tatsuro
AU  - Nobutoki T
AD  - Department of Pediatrics, National Mie Hospital, Mie, Japan. Electronic address: 
      nbtk.kamakura.ped@tenor.ocn.ne.jp.
FAU - Ihara, Toshiaki
AU  - Ihara T
AD  - Department of Pediatrics, National Mie Hospital, Mie, Japan.
LA  - eng
PT  - Journal Article
DEP - 20150930
PL  - United States
TA  - Med Hypotheses
JT  - Medical hypotheses
JID - 7505668
SB  - IM
MH  - Animals
MH  - Astrocytes/cytology/metabolism
MH  - Capillaries/metabolism
MH  - Disease Progression
MH  - Humans
MH  - *Microcirculation
MH  - Motor Neurons/*pathology
MH  - Muscle, Skeletal/physiopathology
MH  - Muscular Atrophy/pathology
MH  - Muscular Atrophy, Spinal/*physiopathology
MH  - Nerve Degeneration/pathology
MH  - Neurons/metabolism/pathology
MH  - Perfusion
MH  - Pericytes/cytology
EDAT- 2015/10/05 06:00
MHDA- 2016/10/19 06:00
CRDT- 2015/10/05 06:00
PHST- 2015/05/05 00:00 [received]
PHST- 2015/09/18 00:00 [revised]
PHST- 2015/09/25 00:00 [accepted]
PHST- 2015/10/05 06:00 [entrez]
PHST- 2015/10/05 06:00 [pubmed]
PHST- 2016/10/19 06:00 [medline]
AID - S0306-9877(15)00371-0 [pii]
AID - 10.1016/j.mehy.2015.09.028 [doi]
PST - ppublish
SO  - Med Hypotheses. 2015 Dec;85(6):842-5. doi: 10.1016/j.mehy.2015.09.028. Epub 2015 
      Sep 30.